WO2021231784A1 - Perk inhibiting imidazolopyrazine compounds - Google Patents

Perk inhibiting imidazolopyrazine compounds Download PDF

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Publication number
WO2021231784A1
WO2021231784A1 PCT/US2021/032324 US2021032324W WO2021231784A1 WO 2021231784 A1 WO2021231784 A1 WO 2021231784A1 US 2021032324 W US2021032324 W US 2021032324W WO 2021231784 A1 WO2021231784 A1 WO 2021231784A1
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Prior art keywords
pyrazin
amino
phenyl
imidazo
methyl
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PCT/US2021/032324
Other languages
French (fr)
Inventor
Alan C. Rigby
Ari NOWACEK
Mark J. Mulvihill
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Hibercell, Inc.
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Publication of WO2021231784A1 publication Critical patent/WO2021231784A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • Embodiments of the present invention relate to novel imidazolopyrazine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.
  • the present invention is in the field of treatment of cancer and viruses (e.g., coronaviruses) and, other diseases and disorders involving protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).
  • PPKR protein kinase R
  • PERK an eIF2 kinase involved in the unfolded protein response (UPR) regulates protein synthesis, aids cells to alleviate the impact of endoplasmic reticulum stress and has been implicated in tumor genesis and cancer cell survival.
  • Tumor cells thrive in a hostile microenvironment caused mainly by nutrient and oxygen limitation, high metabolic demand, and oxidative stress.
  • UPR endoplasmic reticulum
  • the UPR serves as a mechanism for cellular survival whereby cells are able to adapt to cope with ER stress, but under extreme stress the UPR switches the cellular machinery toward apoptosis, contributing to greater tumorigenic potential of cancer cells, tumor metastasis, tumor drug resistance, and the ability of cancer cells to avoid effective immune responses. Tumors are believed to utilize the UPR for survival under stressed conditions such as nutrient deprivation or treatment with chemotherapy.
  • Other stress stimuli that activate UPR include hypoxia, disruption of protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status.
  • ER transmembrane sensors of the UPR There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERN1 and ERN2, respectively); 2) PKR-like ER kinase (PERK, also known as PEK, encoded by EIF2AK3); and 3) the activating transcription factor 6a (encoded by ATF6).
  • IREla/IREip encoded by ERN1 and ERN2, respectively
  • PKR-like ER kinase PKR-like ER kinase
  • PEK also known as PEK, encoded by EIF2AK3
  • 3) the activating transcription factor 6a encoded by ATF6
  • Each of these three sensors is regulated similarly through binding of the ER luminal chaperone protein GRP78 or BiP (encoded by HSPA5).
  • BiP encoded by HSPA5
  • PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphorylate the eukaryotic translation initiation factor 2a (eIF2-a) and regulate translation initiation.
  • Other family members include HRI (EIF2AK1), PKR (EIF2AK2), and GCN2 (EIF2AK4).
  • EIF2AK1 eukaryotic translation initiation factor 2a
  • GCN2 GCN2
  • PERK is an ER transmembrane protein with a stress-sensing domain inside the ER lumen and a cytosolic kinase domain. Upon sensing misfolded proteins, PERK is activated by autophosphorylation and oligomerization through release of BiP/Grp78 from the stress-sensing domain. Activated PERK phosphorylates and activates its downstream substrate, eukaryotic LQLWLDWLRQ ⁇ IDFWRU ⁇ H,) ⁇ ZKLFK ⁇ LQKLELWV ⁇ WKH ⁇ ULERVRPH ⁇ WUDQVODWLRQ ⁇ LQLWLDWLRQ ⁇ FRPSOH[ ⁇ LQ ⁇ RUGHU ⁇ WR ⁇ attenuate protein synthesis.
  • ATF4 activating transcription factor 4 (ATF4).
  • ATF4 mediates the transcription of certain UPR target genes including those for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway proteins which target misfolded proteins for ubiquitination and degradation by the proteasome.
  • ATF4 also causes the expression of the transcription factor C/EBP homologous protein (CHoP), which sensitizes cells to ER stress-mediated apoptosis, providing a pathway for regulated removal of severely stressed cells by the organism.
  • CHoP transcription factor C/EBP homologous protein
  • Phosphorylation of eIF2 results in reduced initiation of general translation due to a reduction in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP.
  • Phosphorylation of eIF2 also increases translation of some mRNAs in a gene specific manner including the transcription factor ATF4.
  • ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient uptake, amino acid metabolism, redox homeostasis, and autophagy. Selective inhibition of the PERK arm of the UPR is expected to profoundly affect tumor cell growth and survival. As such, compounds which inhibit PERK are believed to be useful in treating cancer.
  • Coronaviruses are a family of viruses that are common worldwide and cause a range of illnesses in humans from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause a number of diseases in animals.
  • PERK has been found to be activated during SARS-associated coronavirus (SARS-CoV). Studies have found that PERK may be activated in SARS-CoV through S and 3a proteins. In a separate study, a PERK kinase inhibiting dominant-negative PERK mutant suppressed transcriptional activation of Grp 78 and Grp94 promoters mediated by S proteins of SARS-CoV. Accordingly, compounds that inhibit PERK are believed to be useful in treating viral infections, such as those associated with coronaviruses.
  • Embodiments of the present invention provide methods for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor.
  • the PERK inhibitor is selected from a compound having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF2, or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; each R 1 is independently H, deuterium, halo,
  • the compounds of the present invention are inhibitors of PERK and are believed to be useful in treating cancer. Certain viruses are believed to utilize PERK during protein synthesis and current therapies are ineffective at treating such viruses. Therefore, the compounds of the present invention are also believed to be useful in treating viral infection, for example, infections associated with a coronavirus.
  • the present invention provides a method for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF 2 , or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; each R 1 is independently H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl, C 0-6 alkyl-
  • the present invention yet further provides the PERK inhibitor having the following structure (Ia): wherein: Y is CR 3a R 3b ; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; each R 1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3c , R 3d and R 3e are each independently H
  • the present invention yet further provides the PERK inhibitor having the following structure (Ib): wherein: X is CR 7 or N; each R 1 is independently H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1-12 alkyl, C 0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1-12 alkyl, C 0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; R 3c , R 3d and R 3e are each independently H or alkyl,
  • the present invention yet further provides the PERK inhibitor having the following structure (Ic): wherein: X is CR 7 ; each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G 1 substituents; each R 2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G 2 substituents; R 3b is OR 3c ; R 3c is H or alkyl, optionally substituted by one or more independent G 3 substituents; R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; R 6 is H, alkyl, CD 3 , or CF 3 ; R 7 is
  • each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo
  • each R 2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo
  • R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, or CN
  • R 6 is H, alkyl, CD3, or CF3
  • R 7 is H, deuterium, halo, alkyl, heteroaryl,
  • the present invention yet further provides the PERK inhibitor having the following structure (Ie): wherein: X is CH; each R 1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R 2 is independently H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium or halo; R 5 is H, deuterium halo, methyl, ethyl, isopropyl, , optionally substituted by one or more independent H, deuterium, C 1-6 alkyl, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
  • R 7 is H, chloro, methyl, ethyl, trifluoromethyl, heteroaryl, or CD3.
  • each R 1 is independently H, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, fluoro, or chloro.
  • each R 2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, fluoro, chloro, CF 3 or OCF 3 .
  • R 5 is H, chloro, methyl, or CD3, ethyl, isopropyl, , .
  • R 6 is H, methyl, ethyl, propyl, isopropyl, CD 3 , or CF 3 . In some embodiments, R 6 is other than H.
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, OR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , OC(O)OR 8 , OC(O)NR 8 R 9 , N(R 10 )C(O)R 8 , N(R 10 )C(O)OR 8 , N(R 10 )C(O)NR 8 R 9 , S(O)nR 8 , S(O)nOR 8 , S(O)nNR 8 R 9 , N(R 10 )S(O)nR 8 , N(R 10 )S(O)nOR 8 , or N(R 10 )S(O)nNR 8 R 9 , optional
  • each G 1 , G 2 , G 3 , or G 4 is independently H, deuterium, halo, CN, NO2, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, OR 8 , NR 8 R 9 , C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 9 , OC(O)R 8 , OC(O)OR 8 , OC(O)NR 8 R 9 , N(R 10 )C(O)R 8 , N(R 10 )C(O)OR 8 , N(R 10 )C(O)NR 8 R 9 , S(O) n R 8 , S(O)nOR 8 , S(O)nNR 8 R 9 , N(R 10 )S(O)nR 8 , N(R 10 )S(O)nOR 8 , or N(R 10 )S(O)nNR 8 R 9 , optionally
  • Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents;
  • R 1 is each independently halo or alkyl, optionally substituted by one or more halogen substituents;
  • R 2 is each independently halo, alkyl, or C 0-6 alkyl-O-C 1-12 alkyl, optionally substituted by one or more halogen substituents;
  • R 5 is alkyl or cycloalkyl, optionally substituted by one or more deuterium, hydroxyl, or methyl substituents;
  • R 6 is H or alkyl;
  • R 7 is H, halo, or alkyl, optionally substituted by one or more halogen substituents; and
  • p is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • each R 1 is independently chloro, fluoro, methyl, or trifluoromethyl. In some embodiments, p is 2. In some embodiments, each R 1 is independently fluoro, methyl, or trifluoromethyl.
  • Ar 2 is phenyl. In some embodiments, Ar 2 is phenyl, optionally substituted by one substituent selected from R 2 . In some embodiments, each R 2 is independently methyl, ethyl, fluoro, or trifluoromethoxy. In some embodiments, Ar 2 is phenyl, optionally substituted by two substituents each independently selected from R 2 . In some embodiments, each R 2 is independently fluoro or methyl.
  • Ar 2 is pyridyl, optionally substituted by one substituent selected from R 2 .
  • R 2 is methyl.
  • R 5 is methyl, CD3, .
  • R 6 is H or methyl.
  • R 7 is H, chloro, methyl, or trifluoromethyl.
  • the compound is selected from: N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)
  • Embodiments of the present invention further provide a pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof including one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds, or a pharmaceutically acceptable salt thereof.
  • Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds in combination with an anti-cancer agent, or pharmaceutically acceptable salts thereof.
  • Embodiments of the present invention further provide a compound or pharmaceutically acceptable salt thereof for use in therapy.
  • Embodiments of the present invention further provide a method for treating a viral infection in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of any of the compounds described herein.
  • the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof.
  • the viral infection is associated with an RNA virus.
  • the RNA virus is a single-stranded RNA virus.
  • the single- stranded RNA virus is a coronavirus.
  • the viral infection is associated with a coronavirus.
  • the coronavirus is a coronavirus capable of infecting a human.
  • the coronavirus is an alpha coronavirus.
  • the alpha coronavirus is 229E alpha coronavirus or NL63 alpha coronavirus.
  • the coronavirus is a beta coronavirus.
  • the beta coronavirus is selected from the group consisting of OC43 beta coronavirus, HKU1 beta coronavirus, Severe Acute Respiratory Coronavirus (SARS-CoV), SARS- CoV-2, and Middle East Respiratory Syndrome coronavirus (MERS-CoV).
  • the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the coronavirus is SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV-2. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus infection is COVID-19. Embodiments of the invention further provide methods of treating a coronavirus infection in a patient in need of such treatment, the method comprising administering to the patient an effective amount of any of the compounds described herein.
  • the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof.
  • the methods of treating viral infections described herein further comprise administering an antiviral agent.
  • the antiviral agent is selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol, Atazanavir, Atripla, Balavir, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir (Victrelis), Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Ecoliever, Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir,
  • virus may refer to all types of viruses that replicate inside living cells of other organisms. It may also be cultivated in cell culture. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles, also known as virions, include two or three parts: (i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of lipids that surrounds the protein coat when they are outside a cell.
  • viruses include, but are not limited to, viruses from the following families: Retroviridae (e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses; Picornaviridae (e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus); Caliciviridae (such as strains causing gastroenteritis, including norovirus); Togaviridae (e.g.
  • Retroviridae e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses
  • Picornaviridae e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus
  • Caliciviridae such as strains causing gastroenteritis,
  • alphaviruses including Chikungunya virus, horse encephalitis viruses, Semlica virus, Sindbis virus, Ross fever virus rubella viruses); Flaviridae (e.g. virus hepatitis C virus, dengue virus, yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, Povassan virus and other encephalitis viruses); Coronaviridae (e.g.
  • coronaviruses coronaviruses, severe acute respiratory syndrome virus (SARS), such as SARS- CoV and SARS-CoV-2 (COVID-19), and short-term coronavirus respiratory virus syndrome (MERS)); Rhabdoviridae (e.g., vesicular stomatitis virus, rabies virus); Filoviridae (e.g., Ebola virus, Marburg virus); Paramyxoviridae (e.g.
  • Orthomyxoviridae e.g., influenza viruses
  • Bunyaviridae for example, hantaviruses, Sin Nombre virus, Rift Valley Fever virus, bunyaviruses, phleboviruses and nairoviruses
  • Arenaviridae such as Lassa fever virus and other hemorrhagic fever viruses, Machupo virus, Junin virus
  • Reoviridae e.g., reoviruses, orbiviruses, rotaviruses
  • Birnaviridae Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses, e.g.
  • hepatitis delta pathogen is believed to be a defective satellite in tier hepatitis B).
  • coronavirus may refer to a species in the genera of virus belonging to one of two subfamilies Coronavirinae and Torovirinae in the family Coronaviridae, in the order Nidovirales. Herein these terms may refer to the entire family of Coronavirinae (in the order Nidovirales). Coronaviruses may be defined as enveloped viruses with a positive-sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronaviruses may range from approximately 26 to 32 kilobases.
  • coronavirus is derived from the Latin corona, meaning crown or halo, and refers to the characteristic appearance of virions under electron microscopy (E.M.) with a fringe of large surface projections creating an image reminiscent of a crown. This morphology is created by the viral spike (S) peplomers, which are proteins that populate the surface of the virus and determine host tropism.
  • S viral spike
  • CoVs that naturally infect animals, the majority of which typically infect only one animal species or, at most, a small number of closely related species, but not humans.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • alpha coronaviruses 229E and NL63 examples of coronaviruses known to-date as infecting humans are: alpha coronaviruses 229E and NL63, and beta coronaviruses OC43, HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV.
  • a “symptom” associated with a cancer or a viral infection includes any clinical or laboratory manifestation associated with the cancer or viral infection and is not limited to what the subject can feel or observe.
  • “treating”, e.g., of a cancer or a viral infection encompasses inducing prevention, inhibition, regression, or stasis of the disease or a symptom or condition associated with the cancer or viral infection.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including racemates, enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • the enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • the compounds of the present invention may have spontaneous tautomeric forms.
  • each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
  • This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2 H, 3 H, 13 C, 14 C, 15 N, and/or 18 O.
  • hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
  • compounds described herein may also comprise one or more isotopic substitutions.
  • hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like.
  • a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. It is understood that the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C-14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C. Furthermore, any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein. It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H. Furthermore, any compounds containing 2 H or 3 H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e.
  • R 1 , R 2 , etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
  • C0-4alkyl for example is used to mean an alkyl having 0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration.
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-Cn as in “C1– Cn alkyl” is defined to include groups having 1, 2ising, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C 1 -C 12 alkyl, C 2 -C 12 alkyl, C 3 -C 12 alkyl, C 4 - C12 alkyl and so on.
  • Alkoxy or “Alkoxyl” represents an alkyl group as described above attached through an oxygen bridge.
  • an alkoxy group is represented by C 0-n alkyl-O-C 0-m alkyl in which oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • n is zero
  • -O-C 0-m alkyl is attached directly to the preceding moiety.
  • m zero
  • alkoxy group is “C 0-n alkyl-OH.”
  • alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and so on.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present.
  • C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkenyl As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C2-Cn alkynyl.
  • An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C 4 -C 12 alkynyl and so on.
  • Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • monocycle includes any stable polyatomic carbon ring of up to 12 atoms and may be unsubstituted or substituted.
  • non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aromatic monocycle elements include but are not limited to: phenyl.
  • "bicycle” includes any stable polyatomic carbon ring of up to 12 atoms that is fused to a polyatomic carbon ring of up to 12 atoms with each ring being independently unsubstituted or substituted.
  • non-aromatic bicycle elements include but are not limited to: decahydronaphthalene.
  • aromatic bicycle elements include but are not limited to: naphthalene.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • polycyclic refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4- trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 12 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • alkylheteroaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group.
  • alkylheteroaryl moieties include, but are not limited to, -CH 2 -(C 5 H 4 N), -CH 2 -CH 2 -(C 5 H 4 N) and the like.
  • heterocycle or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like.
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • halogen or “halo” refers to F, Cl, Br, and I.
  • carbonyl refers to a carbon atom double bonded to oxygen.
  • a carbonyl group is denoted as R x C(O)R y where R x and R y are bonded to the carbonyl carbon atom.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfony
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5 th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley- Interscience) 5 th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only methods by which to synthesize or obtain the desired compounds.
  • a pharmaceutical composition comprises the compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically active agent means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.
  • the compounds used in the method of the present invention may be in a salt form.
  • a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
  • “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.
  • the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol.7.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers/diluents.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • parenteral solutions can contain preservatives.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen.
  • the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms. Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine.
  • the compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention.
  • PERK In Vitro Activity Assay In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536 - 1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA). Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli.
  • PSR EIF2AK2
  • PERK EIF2AK3
  • PKR assays contain 14 ng/mL HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ -2.5 ⁇ 3(5. ⁇ DVVD ⁇ V ⁇ FRQWDLQ ⁇ QJ ⁇ P/ ⁇ HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ DSS ⁇ -1.5 uM), and GCN2 DVVD ⁇ V ⁇ FRQWDLQ ⁇ Q0 ⁇ HQ] ⁇ PH ⁇ DQG ⁇ $73 ⁇ .P ⁇ -200 uM).
  • Add test compound initiate the reaction by addition of enzyme, and incubate at room temperature for 45 minutes.
  • HEK293-EGFP-H (HEK293-EGFP-H,) ⁇ FHOOV ⁇ ZHUH ⁇ SODWHG ⁇ DW ⁇ cells/well in 384-well assay plates and incubated overnight at 37°C, 5% CO2.
  • Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% CO2 prior to induction of ER stress by addition of tunicamycin to 1mM for 2 hours.
  • Cells were lysed and TR-FRET was measured in an EnVision plate reader (PerkinElmer). FRET ratio data was normalized to signal from lysates treated with DMSO vehicle control and plotted as percent inhibition against 10-point; 3-fold dilution series of inhibitors.
  • IC50 values were calculated using 4- parameter logistical fitting in XLFit.
  • the compounds of Examples 1 to 187 were tested essentially as described above and exhibited cellular IC50 values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 187 inhibit EIF2a in vitro.
  • the results of exemplary compounds of formula (I) are shown in Table 1.
  • Table 1 Biochemical and cellular IC50 data of Compounds of Formula I:
  • Viral Inhibition Test Compound Preparation A stock concentration of each test article at 10 mM in DMSO was utilized to prepare the working stock dilutions. A working stock was prepared in DMEM2 to JHQHUDWH ⁇ D ⁇ 0 ⁇ VROXWLRQ ⁇ WKHQ ⁇ VHULDOO ⁇ GLOXWHG ⁇ LQ ⁇ '0(0 ⁇ :RUNLQJ ⁇ FRQFHQWUDWLRQV ⁇ RI ⁇ WKH ⁇ WHVW ⁇ articles to be tested was prepared immediately prior to the start of the experiment.
  • Vero E6 cells were cultured in 96 well plates one day prior to the day of the assay. Vero E6 cells were at greater than 90% confluency at the start of the study. Cells were inoculated at a MOI of 0.01 TCID50/cell with SARS-CoV-2 and incubated for one hour in the absence of test articles and control drug. Following 1 hr adsorption, cells were washed and 0.2 mL DMEM2 (DMEM with 2% FBS) containing vehicle, test articles or control drug were added to the respective wells.
  • DMEM2 DMEM with 2% FBS
  • the multiplicity of infection (MOI) was 0.01 TCID50/cell.
  • Table J Reduction In Viral CPE
  • the compound of Example 128 was tested essentially as described above and exhibited a significant reduction in viral cytopathic effect (CPE), as shown in Table J. This data demonstrates that the compounds of Examples 1 to 187 inhibit viral replication in vitro.
  • ER homeostasis External perturbation of ER homeostasis may originate from hypoxia, glucose deficiency and the presence of mutant or viral proteins, which directly or indirectly impair the protein folding capacity within the ER lumen resulting in ER stress conditions [Rozpedek et al., Current Molecular Medicine, 2017].
  • coronavirus (CoV) spike proteins induces ER stress.
  • CoV coronavirus
  • MHV Murine hepatitis virus
  • SARS severe acute respiratory syndrome
  • virus infection triggers a massive production of viral proteins that disrupt ER homeostasis and overload the folding capacities of the ER leading to a stress-induced activation of several eIF2 ⁇ NLQDVHV ⁇ LQFOXGLQJ ⁇ Protein kinase RNA (PKR)-like ER kinase (PERK).
  • PPR Protein kinase RNA
  • PERK branch of the UPR is believed to be activated first in response to ER stress [Szegezdi et al., 2006].
  • the PERK/PKR- eIF2 ⁇ -ATF4-GADD153 pathway plays a central role during productive coronavirus infections and thus approaches to abrogate this pathway may provide a productive mechanism of blocking viral replication and disease propagation. Therefore, the compounds of the present invention are useful in treating viral infection.
  • RBF Round bottom flask
  • NMR nuclear magnetic resonance
  • mHz megahertz
  • DMSO-d6, dimethyl sulfoxide-d6 ;
  • the reaction mixture was purged with argon for 10 min.
  • Palladium(II) acetate (5.77 g, 25.7 mmol) was added, and the mixture was purged with argon for 10 min.
  • the reaction mixture was heated at 95 °C with stirring for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (4 ⁇ 250 mL). The filtrate was washed with water (2 ⁇ 500 mL) and brine (2 ⁇ 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2 Synthesis of 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3): B-1.3 To a stirred solution of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B1-2.1, 28 g, 119 mmol) in THF (70 mL), Water (20 mL), MeOH (50 mL), at room temperature LiOH (6.00 g, 143 mmol) was added and resulting reaction mixture was stirred for 12 h at same temperature. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with water (100 mL). An aqueous layer was washed with EtOAc (200 mL) to remove impurities.
  • EtOAc 200 mL
  • Step- 3 Synthesis of 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2.9): B-2.9 To a stirred solution of acetyl chloride (50 mL) at 0 °C was added 2-hydroxy-2-(3- trifluoro methyl)phenyl)acetic acid (B-1.3, 25.00 g, 113 mmol) portion wise over a period of 30 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h.
  • Step-1 Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-2.3): To a stirred solution of acetyl chloride (1.0 mL) at 0 °C was added 2-(3-fluorophenyl)-2- hydroxyacetic acid (B-1.2, 0.601 g, 3.53 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h.
  • Step-2 Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1): To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 0.558 g, 2.63 mmol) and 4- bromo-3-fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added N,N- diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h.
  • HATU 1-[bis(dimethyl
  • Step-3 Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)- 1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1): To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bis(pinacolato)diboron (0.13 g, 0.52 mmol) and potassium acetate (51 mg, 0.52 mmol.
  • reaction mixture was purged with argon for 10 min. 1,1-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (9.5 mg, 0.01 mmol) was added and the mixture was purged with argon for 10 min.
  • the reaction mixture was exposed to microwave irradiation (SEM Company) at 100 °C for 1 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 ⁇ 15 mL). The filtrate was washed with water (2 ⁇ 10 mL) and brine (2 ⁇ 10 mL).
  • reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 ⁇ 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step-2 Synthesis of N-((3-Chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 0.652 g, 4.14 mmol) in methylene chloride (15.0 mL) were added N,N-diisopropylethylamine (362 mg, 2.80 mmol) followed by acetic anhydride (E-3.1, 320 mg, 0.84 mmol) at 0 o C and stirred for 14 h.
  • (3-chloro-5-methylpyrazin-2-yl)methanamine E-2.1, 0.652 g, 4.14 mmol
  • N,N-diisopropylethylamine 362 mg, 2.80 mmol
  • acetic anhydride E-3.1, 320 mg, 0.84 mmol
  • Step-3 Synthesis of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1, 0.65 g, 3.2 mmol) in acetonitrile (10.0 mL) were added N,N-dimethylformamide (0.3 mL) followed by phosphorous(V) oxychloride (1.5 g, 9.7 mmol) at 0 o C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • Step-4 Synthesis of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1): To a stirred solution of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1, 0.561 g, 3.09 mmol) in N,N-dimethylformamide (8.0 mL) was added N-iodosuccinimide (0.835 g, 3.71 mmol) at room temperature. This reaction mixture was heated to 60 °C and stirred for 3 h.
  • Step-5 Synthesis of 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1): A stirred solution of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1, 0.701 g, 2.28 mmol) in 2.0 M ammonia in isopropanol (200.0 mL) was stirred in an autoclave for 48 h at 120 °C.
  • Step-2 Synthesis of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1): To a stirred solution of N-[(3-chloropyrazin-2-yl)methyl]-2,2,2-trideuterio-acetamide (F-3.1, 40.00 g, 212.7 mmol) in EtOAc (500 mL) were added dimethylformamide (20 mL) followed by phosphoryl chloride (81.3 g, 531.9 mmol) at 0 o C and the resulting reaction mixture was stirred for 16 h at room temperature. After this time, the reaction mixture was poured into mixture of sat.
  • F-4.1 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine
  • Step-3 Synthesis of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.1): To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 10.00 g, 58.8 mmol) in THF (350 mL) at -78 °C, n-butyllithium (2.5 M, 35.2 mL, 88.23 mmol) was added drop-wise and resulting reaction mixture was stirred for 10 min. at the same temperature.
  • methyl iodide (7.5 mL, 117.6 mmol) was added to it and stirred for 15 min. at -78 °C. After this time, the reaction mixture was quenched with sat. ammonium chloride solution (50 mL) at -78 °C. The reaction was warm to room temperature, stirred for 20 min. and extracted with EtOAc (2 x 200 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1): F-6.1 To a stirred solution of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 5.1, 25.00 g, 135 mmol) in dichloromethane (400 mL) was added N-bromosuccinimide (29.10 g, 163 mmol) portion-wise at room temperature and stirred for 1 h at same temperature.
  • Step-5 Synthesis of 1-bromo-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (F-7.1): F-7.1 In a 5 L autoclave, 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1, 30.00 g, 114 mmol) and ammonia (2 M in isopropanol) (2 L) was stirred for 40 h at 120 °C.
  • Step-1 Synthesis of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2): To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 5.00 g, 29.4 mmol) in THF (150 mL) n-butyllithium (2.5 M, 17.6 mL, 44.1 mmol) was added drop-wise at - 78 °C and stirred for 10 min. at the same temperature.
  • Step-2 Synthesis of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 6.2): F-6.2 To a stirred solution of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2, 8.50 g, 41.4 mmol) in DMF (90 mL), N-bromosuccinimide (8.80 g, 49.7 mmol) was added portion- wise at room temperature and stirred for 4 h. After this time, the reaction mixture was quenched with ice cold water (200 mL).
  • Step-3 Synthesis of 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1): To a stirred solution of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.2, 11.20 g, 39.4 mmol) in 1,4-dioxane (150 mL) were added DIPEA (13.1 g, 78.9 mmol) followed by (2,4-dimethoxyphenyl)methanamine (13.90 g, 78.9 mmol) at room temperature.
  • Step-4 Synthesis of 1-bromo-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-2.1): G-2.1 In a 1 L multi neck RBF, 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1, 15.00 g, 36.3 mmol.) and TFA (150 mL) was stirred for 3 h at 80 °C. After this time, the reaction mixture was cooled to room temperature and excess of TFA was distilled off to obtain crude viscous mass.
  • reaction mixture was cooled to room temperature and excess of solvent was distilled off under reduced pressure to obtain crude material.
  • the crude material was basified with aqueous ammonia solution, an aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-2 Synthesis of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3): To a stirred suspension of 2-aminomalonamide (I-2, 17.68 g, 151.16 mmol) and biacetyl (13 g, 151.16 mmol) in water (25 mL) was added aqueous NaOH (50% solution) (15 mL, 188.95 mmol) over a period of 20 min at 10 o C. After completion of addition, resulting reaction mixture was stirred for additional 2 h at the same temperature, pH of reaction mixture was adjusted to 6.0 (by acetic acid).
  • Step-3 Synthesis of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4): To a stirred solution of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3, 12.00 g, 71.85 mmol) in chlorobenzene (60 mL) was added phosphoryl chloride (26.8 mL, 287.4 mmol) at room temperature. The resulting reaction mixture was heated to 60 o C and then added DIEA (37.57 mL, 215.55 mmol) dropwise over 30 min. Then the reaction mixture was stirred at 90 o C for another 3 h.
  • phosphoryl chloride 26.8 mL, 287.4 mmol
  • reaction mixture was cooled to room temperature, poured into mixture of sat. sodium bicarbonate solution (150 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5): I-5 In 450 mL autoclave, to a stirred solution of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4, 8.00 g, 47.9 mmol) in acetic acid (150 mL) was added Raney Nickel (1.6 g) under inert atmosphere and resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (100 psi) at room temperature. After this time, the reaction mixture was passed through the celite bed and washed with acetic acid (2 ⁇ 20 mL).
  • Step-5 Synthesis of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl)acetamide (I-6): To a stirred solution of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5, 5.00 g, 29.13 mmol) in dichloromethane (50 mL) was added DIEA (10.15 mL, 58.27 mmol) followed by acetic anhydride (5.5 mL, 58.27 mmol) at 0 °C. After, that reaction mixture was stirred for 2 h.
  • Step-6 Synthesis of 8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-7): To a stirred solution of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl) acetamide (I-6, 5.00 g, 29.94 mmol.) in acetonitrile (100 mL) were added dimethylformamide (0.50 mL) followed by phosphoryl chloride (8.3 mL, 153.3 mmol) at 0 °C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • Step-7 Synthesis of l-bromo-8-chIoro-3,5 ; 6-trimethylimidazo[l,5- ⁇ ]pyrazin e (I-8):
  • Step-8 Synthesis of 1- bromo-8-chIoro-3,5,6-trimethyIimidazo[1,5-a]pyrazine (1-9):
  • Step-2 Synthesis of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3-oxocyclobutanecarboxamide (J-4): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 3.00 g, 26.3 mmol) in dichloromethane (80 mL) were added N,N-diisopropylethylamine (22.9 mL, 131.5 mmol), T3P (50% in EtOAc) (12 mL, 39.47 mmol) followed by 3-oxocyclobutanecarboxylic acid (J-3, 5.10 g, 26.31 mmol) at 0 o C and stirred for 1 h.
  • Step-3 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-5): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3- oxocyclobutanecarboxamide (J-4, 4.70 g, 18.5 mmol) in EtOAc (80 mL) were added dimethylformamide (3 mL) followed by phosphoryl chloride (5.3 mL, 55.7 mmol) at 0 o C. This reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was cooled to room temperature and poured into mixture of sat.
  • Step-4 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-6): To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-5, 3.00 g, 12.7 mmol) in dimethylformamide (15 mL) was added N- Bromosuccinimide (2.21 g, 12.7 mmol.) at room temperature. This reaction mixture was stirred at room temperature for 40 min.
  • reaction mixture was warmed to –20 °C for 30 min. The mixture was cooled back to –78 °C, aqueous layer extracted with EtOAc (100 mL x 2), combined filtrate was washed with brine (50 mL). The combined organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-6 Synthesis of 3-(8-amino-1-bromo-6-methylimidazo[1,5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-8): In a 450 mL autoclave, a mixture of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3- yl)-1-methylcyclobutanol (J-7, 1.50 g, 4.54 mmol) and ammonia (2M in isopropanol) (150 mL) was stirred for 18 h at 120 °C.
  • the unfolded protein response from stress pathway to homeostatic regulation Science2011, 334, 1081– 1086 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S .; Heindryckx, F.; van Vlierberghe, H.
  • PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis Mol. Cell. Biol. 2012, 32, 5129–5139 Bi, M.; Naczki, C.; Koritzinsky, M.; Fels, D.; Blais, J.; Hu, N.; Harding, H.; Novoa, I.; Varia, M.; R aleigh, J.;Scheuner, D.; Kaufman, R. J.; Bell, J.; Ron, D.; Wouters, B. G.; Koumenis, C. ER stress- regulated translation increases tolerance to extreme hypoxia and promotes tumor growth EMBO J.

Abstract

Provided herein are methods for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor selected from a compound having the structure (I).

Description

PERK INHIBITING IMIDAZOLOPYRAZINE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/024,314, filed May 13, 2020, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Embodiments of the present invention relate to novel imidazolopyrazine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds. The present invention is in the field of treatment of cancer and viruses (e.g., coronaviruses) and, other diseases and disorders involving protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). PERK, an eIF2 kinase involved in the unfolded protein response (UPR) regulates protein synthesis, aids cells to alleviate the impact of endoplasmic reticulum stress and has been implicated in tumor genesis and cancer cell survival. Tumor cells thrive in a hostile microenvironment caused mainly by nutrient and oxygen limitation, high metabolic demand, and oxidative stress. These stresses are known to disrupt the protein folding capacity of the endoplasmic reticulum (ER) eliciting a cellular remediation response known as the UPR. The UPR serves as a mechanism for cellular survival whereby cells are able to adapt to cope with ER stress, but under extreme stress the UPR switches the cellular machinery toward apoptosis, contributing to greater tumorigenic potential of cancer cells, tumor metastasis, tumor drug resistance, and the ability of cancer cells to avoid effective immune responses. Tumors are believed to utilize the UPR for survival under stressed conditions such as nutrient deprivation or treatment with chemotherapy. Other stress stimuli that activate UPR include hypoxia, disruption of protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status. There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERN1 and ERN2, respectively); 2) PKR-like ER kinase (PERK, also known as PEK, encoded by EIF2AK3); and 3) the activating transcription factor 6a (encoded by ATF6). Each of these three sensors is regulated similarly through binding of the ER luminal chaperone protein GRP78 or BiP (encoded by HSPA5). When protein folding demands of the ER exceed capacity, reduced BiP binding results in activation of these ER sensor proteins resulting in the induction of coordinated signaling pathways to increase the folding capacity of the ER and alleviate the underlying stress. Effective responses lead to cell adaptation and survival while irreparable ER stress triggers cell death and apoptosis. PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphorylate the eukaryotic translation initiation factor 2a (eIF2-a) and regulate translation initiation. Other family members include HRI (EIF2AK1), PKR (EIF2AK2), and GCN2 (EIF2AK4). Each eIF2 kinase responds to different cellular stress signals to regulate general translation and gene specific translational control. PERK is an ER transmembrane protein with a stress-sensing domain inside the ER lumen and a cytosolic kinase domain. Upon sensing misfolded proteins, PERK is activated by autophosphorylation and oligomerization through release of BiP/Grp78 from the stress-sensing domain. Activated PERK phosphorylates and activates its downstream substrate, eukaryotic LQLWLDWLRQ^IDFWRU^^Į^^H,)^Į^^^ZKLFK^LQKLELWV^WKH^ULERVRPH^WUDQVODWLRQ^LQLWLDWLRQ^FRPSOH[^LQ^RUGHU^WR^ attenuate protein synthesis. This serves to prevent exacerbation of ER stress by preventing the accumulation of additional misfolded proteins. Although it inhibits general protein synthesis, DFWLYDWHG^H,)^Į^FDXVHV^WKH^WUDQVODWLRQ^RI^VSHFLILF^P51$V^LQYROYHG^LQ^UHVWRULQJ^(5^KRPHRVWDVLV^ including activating transcription factor 4 (ATF4). ATF4 mediates the transcription of certain UPR target genes including those for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway proteins which target misfolded proteins for ubiquitination and degradation by the proteasome. ATF4 also causes the expression of the transcription factor C/EBP homologous protein (CHoP), which sensitizes cells to ER stress-mediated apoptosis, providing a pathway for regulated removal of severely stressed cells by the organism. Phosphorylation of eIF2 results in reduced initiation of general translation due to a reduction in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP. Phosphorylation of eIF2 also increases translation of some mRNAs in a gene specific manner including the transcription factor ATF4. ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient uptake, amino acid metabolism, redox homeostasis, and autophagy. Selective inhibition of the PERK arm of the UPR is expected to profoundly affect tumor cell growth and survival. As such, compounds which inhibit PERK are believed to be useful in treating cancer. Furthermore, Coronaviruses (CoV) are a family of viruses that are common worldwide and cause a range of illnesses in humans from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause a number of diseases in animals. Human coronaviruses 229E, OC43, NL63, HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV are contagious in the human population. PERK has been found to be activated during SARS-associated coronavirus (SARS-CoV). Studies have found that PERK may be activated in SARS-CoV through S and 3a proteins. In a separate study, a PERK kinase inhibiting dominant-negative PERK mutant suppressed transcriptional activation of Grp 78 and Grp94 promoters mediated by S proteins of SARS-CoV. Accordingly, compounds that inhibit PERK are believed to be useful in treating viral infections, such as those associated with coronaviruses. SUMMARY OF THE INVENTION Embodiments of the present invention provide methods for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor. In various embodiments, the PERK inhibitor is selected from a compound having the structure (I):
Figure imgf000004_0001
wherein: Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents; Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; Y is CR3aR3b, C(O), CF2, or CNOR3bb; R3a is H, alkyl, or cycloalkyl; R3b is H, alkyl, OR3c, or NR3dR3e; R3bb is H or alkyl; R4 is H, alkyl, or OH; X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-O-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NO2, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- O-C1-12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION With the current state of medical treatment, patients developing cancer often have a poor prognosis even if the disease is detected early. As such, there remains a significant need for new and effective therapies to treat cancer. The compounds of the present invention are inhibitors of PERK and are believed to be useful in treating cancer. Certain viruses are believed to utilize PERK during protein synthesis and current therapies are ineffective at treating such viruses. Therefore, the compounds of the present invention are also believed to be useful in treating viral infection, for example, infections associated with a coronavirus. The present invention provides a method for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor having the structure (I):
Figure imgf000006_0001
wherein: Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents; Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; Y is CR3aR3b, C(O), CF2, or CNOR3bb; R3a is H, alkyl, or cycloalkyl; R3b is H, alkyl, OR3c, or NR3dR3e; R3bb is H or alkyl; R4 is H, alkyl, or OH; X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-O-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NO2, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- O-C1-12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or
Figure imgf000007_0001
optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition comprising the compound of the present invention, an anti-cancer agent and a pharmaceutically acceptable carrier. The present invention further provides a method for preventing the infection of a cell exposed to a virus or for reducing, retarding or otherwise inhibiting growth and/or replication of a virus in a cell infected with said virus comprising contacting the cell with the compound of the present invention. The present invention yet further provides the PERK inhibitor having the following structure (Ia):
Figure imgf000008_0001
wherein: Y is CR3aR3b; R3a is H or alkyl; R3b is OR3c or NR3dR3e; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents; X is CR7 or N; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. The present invention yet further provides the PERK inhibitor having the following structure (Ib):
Figure imgf000009_0001
wherein: X is CR7 or N; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3a is H or alkyl; R3b is OR3c or NR3dR3e; R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. The present invention yet further provides the PERK inhibitor having the following structure (Ic):
Figure imgf000011_0001
wherein: X is CR7; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G2 substituents; R3b is OR3c; R3c is H or alkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, heteroaryl or alkyl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. The present invention yet further provides the PERK inhibitor having the following structure (Id):
Figure imgf000012_0001
wherein: X is CR7; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, or CN; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, alkyl, heteroaryl, or CD3, wherein the alkyl may be optionally substituted by one or more halo substituents; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. The present invention yet further provides the PERK inhibitor having the following structure (Ie):
Figure imgf000013_0001
wherein: X is CH; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R5 is H, deuterium halo, methyl, ethyl, isopropyl,
Figure imgf000013_0002
, optionally substituted by one or more independent H, deuterium, C1-6alkyl, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. In some embodiments, wherein R7 is H, chloro, methyl, ethyl, trifluoromethyl, heteroaryl, or CD3. In some embodiments, each R1is independently H, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, fluoro, or chloro. In some embodiments, each R2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, fluoro, chloro, CF3 or OCF3. In some embodiments, R5 is H, chloro, methyl, or CD3, ethyl, isopropyl,
Figure imgf000014_0001
,
Figure imgf000014_0002
. In some embodiments, R6 is H, methyl, ethyl, propyl, isopropyl, CD3, or CF3. In some embodiments, R6 is other than H. In some embodiments, each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2. In some embodiments, each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-3alkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2. In some embodiments, Ar1 is phenyl. In some embodiments, Ar2 is phenyl or pyridyl.The present invention yet further provides the PERK inhibitor having the following structure (If):
Figure imgf000015_0001
wherein: Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; R1 is each independently halo or alkyl, optionally substituted by one or more halogen substituents; R2 is each independently halo, alkyl, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more halogen substituents; R5 is alkyl or cycloalkyl, optionally substituted by one or more deuterium, hydroxyl, or methyl substituents; R6 is H or alkyl; R7 is H, halo, or alkyl, optionally substituted by one or more halogen substituents; and p is 1 or 2; or a pharmaceutically acceptable salt thereof. In some embodiments, p is 1. In some embodiments, each R1 is independently chloro, fluoro, methyl, or trifluoromethyl. In some embodiments, p is 2. In some embodiments, each R1is independently fluoro, methyl, or trifluoromethyl. In some embodiments, Ar2 is phenyl. In some embodiments, Ar2 is phenyl, optionally substituted by one substituent selected from R2. In some embodiments, each R2 is independently methyl, ethyl, fluoro, or trifluoromethoxy. In some embodiments, Ar2 is phenyl, optionally substituted by two substituents each independently selected from R2. In some embodiments, each R2 is independently fluoro or methyl. In some embodiments, Ar2 is pyridyl, optionally substituted by one substituent selected from R2. In some embodiments, R2 is methyl. In some embodiments, R5 is methyl, CD3,
Figure imgf000016_0001
. In some embodiments, R6 is H or methyl. In some embodiments, R7 is H, chloro, methyl, or trifluoromethyl. In some embodiments, the compound is selected from: N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(m- tolyl)acetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (m-tolyl)acetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (m-tolyl)acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-(m-tolyl)acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-(m-tolyl)acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-(m-tolyl)acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluorophenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2- fluorophenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2- fluorophenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; or a pharmaceutically acceptable salt thereof. Embodiments of the present invention further provide a pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof including one or more pharmaceutically acceptable carriers, diluents, or excipients. Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds, or a pharmaceutically acceptable salt thereof. Embodiments of the present invention further provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds in combination with an anti-cancer agent, or pharmaceutically acceptable salts thereof. Embodiments of the present invention further provide a compound or pharmaceutically acceptable salt thereof for use in therapy. Embodiments of the present invention further provide a method for treating a viral infection in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of any of the compounds described herein. In some embodiments, the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is associated with an RNA virus. In some embodiments, the RNA virus is a single-stranded RNA virus. In some embodiments, the single- stranded RNA virus is a coronavirus. In some embodiments, the viral infection is associated with a coronavirus. In some embodiments, the coronavirus is a coronavirus capable of infecting a human. In some embodiments, the coronavirus is an alpha coronavirus. In some embodiments, the alpha coronavirus is 229E alpha coronavirus or NL63 alpha coronavirus. In some embodiments, the coronavirus is a beta coronavirus. In some embodiments, the beta coronavirus is selected from the group consisting of OC43 beta coronavirus, HKU1 beta coronavirus, Severe Acute Respiratory Coronavirus (SARS-CoV), SARS- CoV-2, and Middle East Respiratory Syndrome coronavirus (MERS-CoV). In some embodiments, the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV. In some embodiments, the coronavirus is SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV-2. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus infection is COVID-19. Embodiments of the invention further provide methods of treating a coronavirus infection in a patient in need of such treatment, the method comprising administering to the patient an effective amount of any of the compounds described herein. In some embodiments, the PERK kinase modulating compound is a compound of formula I, Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of treating viral infections described herein further comprise administering an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Arbidol, Atazanavir, Atripla, Balavir, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir (Victrelis), Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Ecoliever, Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, a Fusion inhibitor, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Inosine, an Integrase inhibitor, Interferon type I, Interferon type II, Interferon type III, an Interferon, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nitazoxanide, Norvir, a nucleoside analogue, Oseltamivir, Peginterferon alfa-2a, Peginterferon alfa-2b, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, a protease inhibitor, Pyramidine, Raltegravir, Remdesivir, a reverse transcriptase inhibitor, Ribavirin, Rilpivirine (Edurant), Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, a synergistic enhancer, Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tenofovir, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir (Valtrex), Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir (Relenza), Zidovudine, and combinations thereof. As used herein, the term “virus” may refer to all types of viruses that replicate inside living cells of other organisms. It may also be cultivated in cell culture. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles, also known as virions, include two or three parts: (i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of these virus particles range from simple helical and icosahedral forms for some virus species to more complex structures for others. Thus, the term “virus”, as used herein, also encompasses viral particles, particularly infectious particles. Examples of viruses include, but are not limited to, viruses from the following families: Retroviridae (e.g., human immunodeficiency virus 1 (HIV-1), HIV-2, T-cell leukemia viruses; Picornaviridae (e.g., poliovirus, hepatitis A virus, enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses, foot-and-mouth disease virus); Caliciviridae (such as strains causing gastroenteritis, including norovirus); Togaviridae (e.g. alphaviruses, including Chikungunya virus, horse encephalitis viruses, Semlica virus, Sindbis virus, Ross fever virus rubella viruses); Flaviridae (e.g. virus hepatitis C virus, dengue virus, yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, Povassan virus and other encephalitis viruses); Coronaviridae (e.g. coronaviruses, severe acute respiratory syndrome virus (SARS), such as SARS- CoV and SARS-CoV-2 (COVID-19), and short-term coronavirus respiratory virus syndrome (MERS)); Rhabdoviridae (e.g., vesicular stomatitis virus, rabies virus); Filoviridae (e.g., Ebola virus, Marburg virus); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g., influenza viruses); Bunyaviridae (for example, hantaviruses, Sin Nombre virus, Rift Valley Fever virus, bunyaviruses, phleboviruses and nairoviruses); Arenaviridae (such as Lassa fever virus and other hemorrhagic fever viruses, Machupo virus, Junin virus); Reoviridae (e.g., reoviruses, orbiviruses, rotaviruses); Birnaviridae; Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses, e.g. small mouse virus, dog parvovirus, human parvovirus B19 and AAV; Papovaviridae (papilloma viruses, poliomaviruses, BK virus); Adenoviridae (adenoviruses); Herpesviridae (herpes simplex virus (HSV) -1 and HSV-2 ; cytomegalovirus; Epstein-Barr virus; chickenpox virus and other herpes viruses, including HSV-6); Poxviridae (variola viruses, smallpox viruses, poxviruses) and Iridoviridae (such as African swine fever virus), Astroviridae and unclassified for example, the hepatitis delta pathogen is believed to be a defective satellite in tier hepatitis B). As used herein, the terms “coronavirus”, “coronaviruses”, “CoV”, or “CoVs” may refer to a species in the genera of virus belonging to one of two subfamilies Coronavirinae and Torovirinae in the family Coronaviridae, in the order Nidovirales. Herein these terms may refer to the entire family of Coronavirinae (in the order Nidovirales). Coronaviruses may be defined as enveloped viruses with a positive-sense single-stranded RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronaviruses may range from approximately 26 to 32 kilobases. The name “coronavirus” is derived from the Latin corona, meaning crown or halo, and refers to the characteristic appearance of virions under electron microscopy (E.M.) with a fringe of large surface projections creating an image reminiscent of a crown. This morphology is created by the viral spike (S) peplomers, which are proteins that populate the surface of the virus and determine host tropism. There are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta. There are numerous CoVs that naturally infect animals, the majority of which typically infect only one animal species or, at most, a small number of closely related species, but not humans. However, several CoV strains have been identified that have been transmitted from animals to humans. For example, severe acute respiratory syndrome coronavirus (SARS-CoV) can infect people and animals, including monkeys, Himalayan palm civets, raccoon dogs, cats, dogs, and rodents. Middle East respiratory syndrome coronavirus (MERS-CoV) has also been found to infect people and animals, including camels and bats. Examples of coronaviruses known to-date as infecting humans are: alpha coronaviruses 229E and NL63, and beta coronaviruses OC43, HKU1, SARS-CoV, SARS-CoV-2, and MERS-CoV. As used herein, a “symptom” associated with a cancer or a viral infection includes any clinical or laboratory manifestation associated with the cancer or viral infection and is not limited to what the subject can feel or observe. As used herein, “treating”, e.g., of a cancer or a viral infection, encompasses inducing prevention, inhibition, regression, or stasis of the disease or a symptom or condition associated with the cancer or viral infection. The contents of International Application Publication No. WO2018/194885, published October 25, 2018, and International Application Publication No. WO2021/041970, published March 4, 2021, are hereby incorporated by reference. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including racemates, enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. The compounds of the present invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule. This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2H, 3H, 13C, 14C, 15N, and/or 18O. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium); carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N, and the like. In other embodiments, a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. It is understood that the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove. It is understood that where a numerical range is recited herein, the present invention contemplates each integer between, and including, the upper and lower limits, unless otherwise stated. Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein. It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed. In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl. It is understood that substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. As used herein, “C0-4alkyl” for example is used to mean an alkyl having 0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cn as in “C1– Cn alkyl" is defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4- C12 alkyl and so on. “Alkoxy” or “Alkoxyl” represents an alkyl group as described above attached through an oxygen bridge. Thus, an alkoxy group is represented by C0-nalkyl-O-C0-malkyl in which oxygen is a bridge between 0, 1, 2......, n-1, m-1, n or m carbons in a linear or branched arrangement. When n is zero, “-O-C0-malkyl” is attached directly to the preceding moiety. When m is zero, the alkoxy group is “C0-nalkyl-OH.” Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and so on. The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present. Thus, C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on. The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2-Cn alkynyl. An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on. “Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted. As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. As used herein, "heterocycle" or "heterocyclyl" as used herein is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. As herein, "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 12 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl. As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 12 atoms that is fused to a polyatomic carbon ring of up to 12 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene. As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted. The term “arylalkyl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4- trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 12 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like. The term "heterocycle" or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like. The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl. As used herein, the term “halogen” or “halo” refers to F, Cl, Br, and I. As used herein, the term “carbonyl” refers to a carbon atom double bonded to oxygen. A carbonyl group is denoted as RxC(O)Ry where Rx and Ry are bonded to the carbonyl carbon atom. The terms “substitution”, “substituted” and “substituent” refer to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well- known principles of chemical structure connectivity. The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference. The compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only methods by which to synthesize or obtain the desired compounds. The compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley- Interscience) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only methods by which to synthesize or obtain the desired compounds. Another aspect of the invention comprises a compound used in the method of the present invention as a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises the compound of the present invention and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically active agent” means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30th edition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect. The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance. As used herein, “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally. The compounds used in the method of the present invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles. The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect. A dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol.7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier. The compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. The compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug. Gelatin capsules may contain the active ingredient compounds and powdered carriers/diluents. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. For oral administration in liquid dosage form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. In addition, parenteral solutions can contain preservatives. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen. The compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms. Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine. The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention. Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Experimental Details The following materials and methods are used to test the compounds of the present invention. PERK In Vitro Activity Assay (isolated): In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536 - 1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA). Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli. Perform TR-FRET kinase assays in the absence or presence of inhibitors in a reaction buffer consisting of 50 mM HEPES, pH 7.5, 10 mM MgCb, 1.0 mM EGTA, and 0.01% Brij-35, and 100 - 200 nM GFP-eIF2a substrate. PKR assays contain 14 ng/mL HQ]\PH^DQG^^^^^^Ȃ^$73^^.P^^-2.5 ^Ȃ^^^3(5.^DVVD\V^FRQWDLQ^^^^^^QJ^P/^HQ]\PH^DQG^^^^^^Ȃ^$73^^.P^^DSS^-1.5 uM), and GCN2 DVVD\V^FRQWDLQ^^^Q0^HQ]\PH^DQG^^^^^Ȃ^$73^^.P^^-200 uM). Add test compound, initiate the reaction by addition of enzyme, and incubate at room temperature for 45 minutes. Stop the reaction by addition of EDTA to a final concentration of 10 mM, add Terbium-labelled phospho-eIF2a antibody at a final concentration of 2 nM, and incubate for 90 minutes. Monitor the resulting fluorescence in an EnVison® Multilabel reader (PerkinElmer, Waltham, MA). Determine TR-FRET ratios and the resulting IC50 values using a 4-parameter nonlinear logistic equation as shown: Y = (A+((B- A)/(l+((C/x)AD)))) where, Y = % specific inhibition, A = Bottom of the curve, B = Top of the curve, C = absolute IC50 (concentration causing 50% inhibition), and D = hill slope. The compounds of Examples 1 to 187 were tested essentially as described above and exhibited IC50 values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 187 inhibit isolated PERK enzyme activity in vitro. PERK Cellular Assay: Stable cell lines were created in HEK293 cells using lentiviral particles harboring an expression vector for GFP- H,)^Į^^&HOOV^ZHUH^VHOHFWHG^XVLQJ^SXURP\FLQ^DQG^HQULFKHG^XVLQJ^ fluorescence activated cell sorting against GFP. HEK293-EGFP-H,)^Į^FHOOV^ZHUH^SODWHG^DW^^^^^^ cells/well in 384-well assay plates and incubated overnight at 37°C, 5% CO2. Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% CO2 prior to induction of ER stress by addition of tunicamycin to 1mM for 2 hours. Cells were lysed and TR-FRET was measured in an EnVision plate reader (PerkinElmer). FRET ratio data was normalized to signal from lysates treated with DMSO vehicle control and plotted as percent inhibition against 10-point; 3-fold dilution series of inhibitors. IC50 values were calculated using 4- parameter logistical fitting in XLFit. The compounds of Examples 1 to 187 were tested essentially as described above and exhibited cellular IC50 values shown in Table 1. These data demonstrate that the compounds of Examples 1 to 187 inhibit EIF2a in vitro. The results of exemplary compounds of formula (I) are shown in Table 1. Key: A is 0.001 to 0.025 µM; B is 0.026 to 0.050 µM; C is 0.051 to 0.100 µM; D is 0.101 to 0.250 µM; E is 0.251 to 0.500 µM; F is 0.501 to 1.00 µM; G is 1.001 µM to 2.00 µM; H is 2.001 µM to 3.00 µM; I is 3.001 to 4.00 µM; J is 4.001 to 5.00 µM, K is >5.00 µM; and N/A is “not available”. Table 1: Biochemical and cellular IC50 data of Compounds of Formula I:
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Viral Inhibition Test Compound Preparation: A stock concentration of each test article at 10 mM in DMSO was utilized to prepare the working stock dilutions. A working stock was prepared in DMEM2 to JHQHUDWH^D^^^^^0^VROXWLRQ^WKHQ^VHULDOO\^GLOXWHG^LQ^'0(0^^^:RUNLQJ^FRQFHQWUDWLRQV^RI^WKH^WHVW^ articles to be tested was prepared immediately prior to the start of the experiment. Basis for Selection of Virus Inoculation Doses: Cells were infected with USA-WA1/2020 (SARS-CoV-2), virus at a MOI of 0.01 which produces cytopathic effect (CPE) 72 hours post inoculation. Basis for Selection of Test Article Dose Levels: The dose-dependent anti-viral effect of each compound was tested individually. For individual testing, the compounds were tested at eight FRQFHQWUDWLRQV^ZLWK^D^VWDUWLQJ^FRQFHQWUDWLRQ^RI^^^^^0^IRU^DOO^FRPSRXQGV^^Table I). Three-fold serial dilutions was prepared across the plate in DMEM2. Table I: Testing Concentrations
Figure imgf000061_0001
Experimental Design: Efficacy for each compound was tested. Each of the concentrations were evaluated in triplicate for efficacy. Vero E6 cells were cultured in 96 well plates one day prior to the day of the assay. Vero E6 cells were at greater than 90% confluency at the start of the study. Cells were inoculated at a MOI of 0.01 TCID50/cell with SARS-CoV-2 and incubated for one hour in the absence of test articles and control drug. Following 1 hr adsorption, cells were washed and 0.2 mL DMEM2 (DMEM with 2% FBS) containing vehicle, test articles or control drug were added to the respective wells. The plates were then incubated in a humidified chamber at 37°C ± 2°C in 5 ± 2% CO2. At 72 hours ± 4 hrs post inoculation, wells were evaluated for cytotoxicity/cytoprotection by neutral red assay. Cell Culture: African green monkey kidney (Vero E6) cells were maintained in Dulbecco’s Minimum Essential Medium with 10% fetal calf serum. All growth media contains heat-inactivated fetal calf serum and antibiotics. Challenge Viruses: 2019 Novel Coronavirus, Isolate USA-WA1/2020 (SARS-CoV-2) were used. 7KH^YLUXV^ZDV^VWRUHG^DW^DSSUR[LPDWHO\^^^-65°C prior to use. The multiplicity of infection (MOI) was 0.01 TCID50/cell. Table J: Reduction In Viral CPE
Figure imgf000062_0001
The compound of Example 128 was tested essentially as described above and exhibited a significant reduction in viral cytopathic effect (CPE), as shown in Table J. This data demonstrates that the compounds of Examples 1 to 187 inhibit viral replication in vitro. HPLC Conditions: Method A Column: Polaris C18-A 2.6 µm C18 (100 × 3.0 mm) Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid Mobile Phase B: Acetonitrile containing 0.05% v/v Trifluoroacetic Acid Detection: 230 nm Method A Gradient
Figure imgf000062_0002
Method B Column: Eclipse plus C183.5 µm C18 (100 × 4.6 mm) Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid Mobile Phase B: Acetonitrile containing 0.05% v/v Trifluoroacetic Acid Detection: 254 nm Method B Gradient
Figure imgf000063_0001
Method C Column: Eclipse plus C183.5 µm C18 (100 × 4.6 mm) Mobile Phase A: Water containing 0.05% v/v Trifluoroacetic Acid Mobile Phase B: Acetonitrile containing 0.05% v/v Trifluoroacetic Acid Detection: 270 nm Method C Gradient
Figure imgf000063_0002
Method D Column: Luna C18(2) 5 µm C18 (150 × 4.6 mm) Mobile Phase A: Water containing 0.1% v/v Trifluoroacetic Acid Mobile Phase B: Acetonitrile containing 0.1% v/v Trifluoroacetic Acid Detection: 254 nm Method D Gradient
Figure imgf000063_0003
Figure imgf000064_0001
Analytical SFC Conditions: Method A Column: Chiralcel OX-H Mobile Phase: 30% Methanol in CO2 Temperature: 40 °C Run Time: 10.0 min Detection: 210 nm Method B Column: Chiralpak IC Mobile Phase: 30% Methanol in CO2 Temperature: 40 °C Run Time: 8.0 min Detection: 215 nm Method C Column: Chiralcel OD-H Mobile Phase: 25% Methanol in CO2 Temperature: 40 °C Run Time: 10.0 min Detection: 215 nm Method D Column: Chiralpak IA Mobile Phase: 40% Methanol in CO2 Temperature: 40 °C Run Time: 8.0 min Detection: 210 nm Method E Column: Chiralcel OJ-H Mobile Phase: 30% Methanol in CO2 Temperature: 40 °C Run Time: 8.0 min Detection: 254 nm PERK Viral Inhibition The Endoplasmic Reticulum (ER) is the protein quality control system that plays a fundamental role in cell growth, homeostasis and protection. External perturbation of ER homeostasis may originate from hypoxia, glucose deficiency and the presence of mutant or viral proteins, which directly or indirectly impair the protein folding capacity within the ER lumen resulting in ER stress conditions [Rozpedek et al., Current Molecular Medicine, 2017]. The expression of coronavirus (CoV) spike proteins induces ER stress. In addition to CoV, Murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS) are two of the better studied representatives of the family Coronaviridae. The dependence on host protein synthesis machinery makes viral mRNAs sensitive to various stress-induced translation repression mechanisms. In support of this, mechanistic studies of CoV infection have demonstrated that several cytokines and chemokines are transiently induced in vitro and in vivo. Importantly, SARS-CoV and MHV viral spike protein expression robustly induce ER stress and Cxcl2 mRNA transcription during infection as observed in vitro [Versteeeg et al., J. Virology. 2007]. Continued efforts to abrogate spike protein-host interactions, including the use of neutralizing antibodies and mutated viral spike proteins that prevent spike protein development, have demonstrated ER stress and more generally UPR (unfolded protein response) induction a key mechanism in viral infection and host-virus infections and pathogenesis. To better define mechanisms driving viral infection, laboratories have studied and demonstrated that virus infection triggers a massive production of viral proteins that disrupt ER homeostasis and overload the folding capacities of the ER leading to a stress-induced activation of several eIF2Į^NLQDVHV^ LQFOXGLQJ^^Protein kinase RNA (PKR)-like ER kinase (PERK). The PERK branch of the UPR is believed to be activated first in response to ER stress [Szegezdi et al., 2006]. While several laboratories have worked to define the mechanism of PERK activation it is triggered by the dissociation from ER chaperon GRP78/BiP, followed by oligomerization and auto- SKRVSKRU\ODWLRQ^ >/HH^^ 0HWKRGV^^ ^^^^@^^ $FWLYDWHG^ 3(5.^ WKHQ^ SKRVSKRU\ODWHV^ WKH^ Į-subunit of HXNDU\RWLF^LQLWLDWLRQ^IDFWRU^^^^H,)^Į^^^3KRVSKRU\ODWHG^H,)^Į^IRUPV^D^VWDEOH^FRPSOH[^ZLWK^DQG^LQKLELWV^ protein turnover of eIF2B, a guanine nucleotide exchange factor that recycles inactive eIF2-GDP to active eIF2-GTP [Teske et al., Mol. Biol. Cell, 2011]. This results in a general shutdown of cellular protein synthesis and reduces the protein flux into the ER [Ron and Walter, 2007]. Accumulation of misfolded protein and the ensuing induction of ER stress, also referred to as proteotoxicity, contributes to the etiology of diseases including diabetes, cancer, neurodegenerative disorders and viral infection [Schroder & Kaufman, Annu Rev Biochem., 2005; Marciniak & Ron, Physiol Rev., 2006: Wek & Cavener, Antioxid Redox Signal, 2007; Oakes, American J. Pathol., 2020, Jordan et al., 2002; Baltzis et al, 2004; Cheng et a!., 2005], Viruses have adopted counter measures that inhibit PERK-mediated translation attenuation via direct binding and inhibition of the kinase activity of PERK, which restores viral protein translation [Pavio et al, 2003; Mulvey et al, 2007], Translation attenuation has been widely observed as a defense mechanism employed by host cells to prevent viral infection. By reducing protein translation of the viral proteins, virus replication is hampered and the spread of infection is paused, providing time for the immune system to mount an effective antiviral response [Fung & Liu, Frontiers in Microbiology, 2014],
Separately, it has been demonstrated that SARS-CoV infections result in PKR, PERK, and eIF2α phosphorylation events that are readily detectable in virus-infected cells [Krahling et al,, 2009], Their knock-down of PKR via morpholino oligomers did not impact SARS-CoV-induced eIF2α phosphorylation but did significantly inhibit SARS-CoV-induced apoptosis [Krahling et al,, 2009], One hypothesis is that eIF2α is phosphorylated by PERK in SARS-CoV-infected cells, a hypothesis that is supported by the overexpression of SARS-CoV accessory' protein 3a that has been shown to activate the PERK pathway [Minakshi et al., 2009],
Accordingly, without wishing to be bound by theory', it is contemplated that the PERK/PKR- eIF2α-ATF4-GADD153 pathway plays a central role during productive coronavirus infections and thus approaches to abrogate this pathway may provide a productive mechanism of blocking viral replication and disease propagation. Therefore, the compounds of the present invention are useful in treating viral infection.
Abbreviations: RBF: Round bottom flask;
NMR: nuclear magnetic resonance; mHz: megahertz;
DMSO-d6,: dimethyl sulfoxide-d6 ;
CDCl3: demeaned chloroform; δ: chemical shift;
MS: mass spectrometry; HPLC: high performance liquid chromatography; SFC: Supercritical fluid chromatography m/z: mass-to-charge ratio; [M+H]: molecular ion peak in mass spectrum; ESI: electrospray ionization; ESI+: electrospray ionization positive mode; ESI-: electrospray ionization negative mode; rt or RT: room temperature: min: minute(s); h: hour(s) mg: milligram; g: gram; kg: kilogram; mL: milliliter; L: liter; mmol: millimole; PM: micromole; MTBE: methyl tert-butyl ether; THF: tetrahydrofuran; HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; DIPEA or DIEA: N,N-diisopropylethylamine; HOBt: hydroxybenzotriazole; Pd(dppf)Cl2: [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II); EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Togni’s reagent: 1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one; T3P: Propanephosphonic acid anhydride. Scheme A:
Figure imgf000068_0001
Compounds of Formula A-2 where Ar2 = phenyl and R2 = 3-methyl can be synthesized as described below for compound A-2.1:
Figure imgf000068_0003
Sythesis of 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1):
Figure imgf000068_0002
To a stirred solution of tricyclohexylphosphine (7.18 g, 25.7 mmol) in 1,4-dioxane (1.2 L) under argon atmosphere were added bis(pinacolato)diboron (89.62 g, 352.9 mmol) and potassium acetate (62.98 g, 641.7 mmol), followed by 4-bromo-3-methylaniline (A-1.1, 60.00 g, 320.8 mmol). The reaction mixture was purged with argon for 10 min. Palladium(II) acetate (5.77 g, 25.7 mmol) was added, and the mixture was purged with argon for 10 min. The reaction mixture was heated at 95 °C with stirring for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (4 × 250 mL). The filtrate was washed with water (2 × 500 mL) and brine (2 × 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1, 44.80 g, yield: 60%) as a pale brown solid: ESI (m/z) 234 [C13H20BNO2 + H]+. The compounds of formula A-2 (Table A) can be synthesized according to the procedures described for compound A-2.1: Table A: Compounds A-2:
Figure imgf000069_0001
Figure imgf000070_0003
Scheme B:
Figure imgf000070_0001
Compounds of Formula B-2 where Ar1 = 3-chlorophenyl and R3a = H can be synthesized as described below for compound B-2.1:
Figure imgf000070_0002
Synthesis of 2-acetoxy-2-(3-chlorophenyl)acetic acid (B-2.1):
Figure imgf000071_0001
To a stirred solution of acetyl chloride (2.0 mL) at 0 °C was added 2-(3-chlorophenyl)-2- hydroxyacetic acid (B-1.1, 2.00 g, 10.6 mmol) portion wise over a period of 10 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to get crude material followed by co-distilled with hexanes to afford 2-acetoxy-2-(3-chlorophenyl)acetic acid (B-2.1, 2.10 g, yield: 86%) as a white solid; 1H NMR (400 MHz, DMSO-d6): G 7.54-7.44 (m, 4H), 5.87 (s, 1H), 2.14 (s, 3H); ESI (m/z) 228.6 [C10H9ClO4 + H]+. The compounds of formula B-2 (Table B) can be synthesized according to the procedures described for compound B-2.1: Table B: Compounds B-2:
Figure imgf000071_0002
Figure imgf000072_0003
Scheme B1:
Figure imgf000072_0001
Compounds of Formula B-2 where Ar1 = 3-trifluoromethylphenyl and R3a = H can be synthesized as described below for compound B-2.9:
Figure imgf000072_0002
St 1 S th i f th l 2h d 2(3(tifl th l) h l) tt (B121)
Figure imgf000073_0001
B1-2.1 To a stirred solution of 3-(trifluoromethyl)benzaldehyde (B1-1.1, 25.00 g, 143 mmol) at 0 °C was added ZnI ( 4.50 g, 14.3 mmol), followed drop wise addition of trimethylsilyl cyanide (17.0 mL, 172.0 mmol) and resulting reaction mixture was stirred at 0 °C for 2 h. After this time, to the above reaction mixture HCl (4N in MeOH) (100 mL) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with saturated NaHCO3 solution up to pH ~8, then added EtOAc (200 mL). The organic layer was washed with water (4 × 200 mL), followed by brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford methyl 2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetate (B1-2.1, 28 g, yield: 83%) as a yellow liquid; ESI (m/z) 235 [C10H9F3O3+H]-. Step 2: Synthesis of 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3):
Figure imgf000073_0002
B-1.3 To a stirred solution of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B1-2.1, 28 g, 119 mmol) in THF (70 mL), Water (20 mL), MeOH (50 mL), at room temperature LiOH (6.00 g, 143 mmol) was added and resulting reaction mixture was stirred for 12 h at same temperature. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with water (100 mL). An aqueous layer was washed with EtOAc (200 mL) to remove impurities. Then water layer was acidified with 2N HCl (pH ~ 2), an aqueous layer extracted with EtOAc(2 x 150 mL). Combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3, 25.00 g, yield: 95%) as a color less liquid: ESI (m/z) 219.1 [C9H7F3O3-H]-. Step- 3: Synthesis of 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2.9):
Figure imgf000074_0001
B-2.9 To a stirred solution of acetyl chloride (50 mL) at 0 °C was added 2-hydroxy-2-(3- trifluoro methyl)phenyl)acetic acid (B-1.3, 25.00 g, 113 mmol) portion wise over a period of 30 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to get crude material followed by co-distilled with hexanes to afford 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2.9, 21.00 g, yield: 70%) as a white solid; 1H NMR (400 MHz, DMSO-d6): G 7.80 (t, J = 8.0 Hz, 3H), 7.68 (t, J = 8.0 Hz, 1H), 6.00 (s, 1H), 2.15 (s, 3H); ESI (m/z) 262.2 [C11H9F3O4 + H]+. The compounds of formula B-2 (Table B1) can be synthesized according to the procedures described for compound B-2.9: Table B1: Compounds B-2:
Figure imgf000074_0002
Figure imgf000075_0003
Scheme C:
Figure imgf000075_0001
Compounds of Formula C-2 where Ar2 = phenyl, R2 = 3-F, Y2 = Br, R3a = H, Ar1 = phenyl- R1 and R1 = 3-F can be synthesized as described below for compound C-2.1:
Figure imgf000075_0002
Step-1: Synthesis of 2-acetoxy-2-(3-fluorophenyl)acetic acid (C-2.3):
Figure imgf000076_0001
To a stirred solution of acetyl chloride (1.0 mL) at 0 °C was added 2-(3-fluorophenyl)-2- hydroxyacetic acid (B-1.2, 0.601 g, 3.53 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the reaction mixture was concentrated to crude under vacuum and co-distilled with hexanes to afford 2-acetoxy-2-(3- fluorophenyl)acetic acid (B-2.3, 0.70 g, yield: 94%) as a white solid: ESI (m/z) 211 [C10H9FO4-H]-. Step-2: Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1):
Figure imgf000076_0002
To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 0.558 g, 2.63 mmol) and 4- bromo-3-fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added N,N- diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h. After this time, the reaction mixture was diluted with dichloromethane (6.0 mL) and washed with water (4 × 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 4% methanol/dichloromethane) to afford 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 500 mg, yield: 60%) as a pale brown solid: ESI (m/z) 385[C16H12BrF2NO3]+. Step-3: Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)- 1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1):
Figure imgf000077_0001
To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-1.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bis(pinacolato)diboron (0.13 g, 0.52 mmol) and potassium acetate (51 mg, 0.52 mmol. The reaction mixture was purged with argon for 10 min. 1,1-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (9.5 mg, 0.01 mmol) was added and the mixture was purged with argon for 10 min. The reaction mixture was exposed to microwave irradiation (SEM Company) at 100 °C for 1 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 × 15 mL). The filtrate was washed with water (2 × 10 mL) and brine (2 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 2- ((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(3-fluorophenyl)-2- oxoethyl acetate (C-2.1, 50 mg, yield: 60%) as a pale brown solid: ESI (m/z) 432 [C22H24BF2NO5 + H]+. The compounds of formula C-2 (Table C) can be synthesized according to the procedures described for compound C-2.1: Table C: Compounds C-2:
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0003
Scheme D:
Figure imgf000082_0001
Compounds of Formula D-1 where Ar2 = phenyl, R2 = 3-methyl, R3a = H, Ar1 = phenyl-R1 and R1 = 3-F can be synthesized as described below for compound D-1.1:
Figure imgf000082_0002
Synthesis of 2-(3-Fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetamide (D-1.1):
Figure imgf000083_0001
To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A-2.1, 0.298 g, 1.28 mmol) and 2-(3-fluorophenyl)-2-hydroxyacetic acid (B-1.2, 0.196 g, 1.15 mmol) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (0.586, 1.54 mmol) at 0 oC. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 × 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 4% methanol/dichloromethane) to afford 2-(3-fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)acetamide (D-1.1, 0.25 g, yield: 52%) as a pale brown solid: ESI (m/z) 386 [C21H25BFNO4+H]+. The compounds of formula D-1 (Table D) can be synthesized according to the procedures described for compound D-1.1: Table D: Compounds D-1:
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0002
Scheme E:
Figure imgf000088_0001
Compounds of Formula E-7 where R3 = methyl, R6 = methyl and Y1 = I can be synthesized as described below for compound E-7.1:
Figure imgf000089_0001
To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (E-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth and washed with ethyl acetate (2 × 20 mL). The organic layer was concentrated under vacuum and diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous layer was concentrated to give the crude product, which was triturated with acetonitrile (5 mL) to afford (3- chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 1.0 g, yield: 78%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+. Step-2: Synthesis of N-((3-Chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1):
Figure imgf000089_0002
To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 0.652 g, 4.14 mmol) in methylene chloride (15.0 mL) were added N,N-diisopropylethylamine (362 mg, 2.80 mmol) followed by acetic anhydride (E-3.1, 320 mg, 0.84 mmol) at 0 oC and stirred for 14 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and washed with water (4 × 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and d d d d Th d i l ifi d b l h h (silica gel, 1% methanol/dichloromethane) to afford N-((3-chloro-5-methylpyrazin-2- yl)methyl)acetamide (E-4.1, 0.65 g, yield: 65%) as a pale brown solid: ESI (m/z) 200 [C8H10ClN3O+H]+. Step-3: Synthesis of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1):
Figure imgf000090_0002
To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1, 0.65 g, 3.2 mmol) in acetonitrile (10.0 mL) were added N,N-dimethylformamide (0.3 mL) followed by phosphorous(V) oxychloride (1.5 g, 9.7 mmol) at 0 oC. This reaction mixture was heated to 80 °C and stirred for 2 h. After this time, the reaction mixture was cooled to room temperature and poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80% ethyl acetate/hexanes) to afford 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1, 0.51 g, yield: 86%) as a pale brown solid: ESI (m/z) 182 [C8H8ClN3 +H]+. Step-4: Synthesis of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1):
Figure imgf000090_0001
To a stirred solution of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1, 0.561 g, 3.09 mmol) in N,N-dimethylformamide (8.0 mL) was added N-iodosuccinimide (0.835 g, 3.71 mmol) at room temperature. This reaction mixture was heated to 60 °C and stirred for 3 h. After this time, the reaction mixture was cooled to room temperature, diluted with methylene chloride (15 mL), and adsorbed onto silica gel (100-200 mesh). The crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexanes) to afford 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1, 0.70 g, yield: 80%) as yellow solid: ESI (m/z) 308 [C8H7ClIN3 +H]+. Step-5: Synthesis of 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1):
Figure imgf000091_0001
A stirred solution of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1, 0.701 g, 2.28 mmol) in 2.0 M ammonia in isopropanol (200.0 mL) was stirred in an autoclave for 48 h at 120 °C. After this time, the reaction mixture was cooled to room temperature, and solids were filtered to afford 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1, 0.50 g, yield: 76%) as a pale brown solid: ESI (m/z) 289 [C8H9IN4 +H]+. The compounds of formula E-7 (Table E) can be synthesized according to the procedures described for compound E-7.1: Table E: Compound E-7:
Figure imgf000091_0002
Scheme F:
Figure imgf000092_0001
Compounds of Formula F-7 where R5 = methyl, R3 = CD3, and Y1 = Br can be synthesized as described below for compound F-7.1:
Figure imgf000092_0002
F-3.1 To a stirred solution of (3-chloropyrazin-2-yl)methanamine dihydrochloride (F-1.1, 50.00 g, 231.4 mmol) in THF (700 mL) were added N,N-diisopropylethylamine (121 mL, 694.4 mmol) followed by acetic acid-d3 (F-2.1, 21.80 g, 347.1 mmol) and EDC.HCl (66.00 g, 347.1 mmol) at 0 oC and stirred for 4 h. After this time, the reaction mixture was quenched with water (150 mL), an aqueous layer extracted with EtOAc (3 × 500 mL). The combined organic layer was dried over fil d d d b i d il hih ifid b l chromatography (silica gel, 100% ethyl acetate/hexanes) to afford N-[(3-chloropyrazin-2- yl)methyl]-2,2,2-trideuterio-acetamide (F-3.1, 40.00 g, yield: 91%) as an off white solid; ESI (m/z) 188 [C7H5D3ClN3O +H]+. Step-2: Synthesis of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1):
Figure imgf000093_0001
To a stirred solution of N-[(3-chloropyrazin-2-yl)methyl]-2,2,2-trideuterio-acetamide (F-3.1, 40.00 g, 212.7 mmol) in EtOAc (500 mL) were added dimethylformamide (20 mL) followed by phosphoryl chloride (81.3 g, 531.9 mmol) at 0 oC and the resulting reaction mixture was stirred for 16 h at room temperature. After this time, the reaction mixture was poured into mixture of sat. sodium bicarbonate solution (500 mL), EtOAc (500 mL) at 10 °C and then adjusted pH of reaction mixture up to ~8. The organic layer was separated, washed with sodium bicarbonate solution (500 mL), brine (100 mL), combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80-100% ethyl acetate/hexanes) to afford 8-chloro-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-4.1, 30.00 g, yield: 83%) as a light yellow solid; ESI (m/z) 171 [ C7H3D3ClN3 +H]+. Step-3: Synthesis of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.1):
Figure imgf000093_0002
To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 10.00 g, 58.8 mmol) in THF (350 mL) at -78 °C, n-butyllithium (2.5 M, 35.2 mL, 88.23 mmol) was added drop-wise and resulting reaction mixture was stirred for 10 min. at the same temperature. Then, methyl iodide (7.5 mL, 117.6 mmol) was added to it and stirred for 15 min. at -78 °C. After this time, the reaction mixture was quenched with sat. ammonium chloride solution (50 mL) at -78 °C. The reaction was warm to room temperature, stirred for 20 min. and extracted with EtOAc (2 x 200 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 70-100% ethyl acetate/hexanes) to afford 8-chloro-5-methyl-3- (trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.1, 7.50 g, yield: 69%) as a pale yellow solid; ESI (m/z) 185 [C8H5D3ClN3 +H]+. Step-4: Synthesis of 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1):
Figure imgf000094_0001
F-6.1 To a stirred solution of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 5.1, 25.00 g, 135 mmol) in dichloromethane (400 mL) was added N-bromosuccinimide (29.10 g, 163 mmol) portion-wise at room temperature and stirred for 1 h at same temperature. After this time, the reaction mixture was diluted with dichloromethane (400 mL), washed with water (400 mL) and brine (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get crude material which was washed with 20% ethyl acetate in hexanes to obtain 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-6.1, 31.70 g, yield: 89%) as a yellow solid; ESI (m/z) 263 [C8H4D3BrClN3+H]+. Step-5: Synthesis of 1-bromo-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (F-7.1):
Figure imgf000094_0002
F-7.1 In a 5 L autoclave, 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1, 30.00 g, 114 mmol) and ammonia (2 M in isopropanol) (2 L) was stirred for 40 h at 120 °C. After this time, the reaction mixture was cooled to room temperature, excess of solvent was distilled off to obtain crude material, which was washed with 20% acetonitrile in water (150 mL) and dried under vacuum to afford 1-bromo-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (F- 7.1, 23.00 g, 83%) as a pale brown solid; ESI (m/z) 244 [C8H6D3BrN4 +H]+. The compounds of formula F-7 (Table F) can be synthesized according to the procedures described for compound F-7.1: Table F: Compound F-7:
Figure imgf000095_0002
Scheme G:
Figure imgf000095_0001
Compounds of Formula G-2 where R5 = Cl, R3 = CD3, Y1 = Br, and R8 = (2,4- dimethoxyphenyl) methanamino can be synthesized as described below for compound G-2.1:
Figure imgf000096_0001
G-1.1
Step-1: Synthesis of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2):
Figure imgf000097_0001
To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 5.00 g, 29.4 mmol) in THF (150 mL) n-butyllithium (2.5 M, 17.6 mL, 44.1 mmol) was added drop-wise at - 78 °C and stirred for 10 min. at the same temperature. Then, the solution of hexachloroethane (10.40 g, 44.1 mmol) in THF (20 mL) was added drop-wise to the above reaction mixture at -78 °C and stirred for 15 min. at same temperature. After this time, the reaction mixture was quenched with sat. aqueous ammonium chloride solution (50 mL) at -78 °C. The reaction was warm to room temperature and stirred for 20 min, an aqueous layer was extracted with EtOAC (2 u 200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 70-100% ethyl acetate/hexanes) to afford 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-5.2, 4.20 g, yield: 69%) as a pale yellow solid; ESI (m/z) 204 [C7H2D3Cl2N3 +H]+. Step-2: Synthesis of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 6.2):
Figure imgf000097_0002
F-6.2 To a stirred solution of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-5.2, 8.50 g, 41.4 mmol) in DMF (90 mL), N-bromosuccinimide (8.80 g, 49.7 mmol) was added portion- wise at room temperature and stirred for 4 h. After this time, the reaction mixture was quenched with ice cold water (200 mL). Solid was precipitated out, was filtered, washed with water (100 mL), dried under vacuum to obtained 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.2, 11.20 g, yield: 95%) as an off white solid; ESI (m/z) 282 [C7HD3BrCl2N3+H]+. Step-3: Synthesis of 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1):
Figure imgf000098_0001
To a stirred solution of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.2, 11.20 g, 39.4 mmol) in 1,4-dioxane (150 mL) were added DIPEA (13.1 g, 78.9 mmol) followed by (2,4-dimethoxyphenyl)methanamine (13.90 g, 78.9 mmol) at room temperature. This reaction mixture was stirred for 48 h at room temperature. After this time, the reaction mixture was quenched with ice cold water (200 mL). Solid was precipitated out, was filtered, washed with water (100 mL), dried under vacuum to obtain 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1, 15.20 g, yield: 92%) an off white solid; ESI (m/z) 414 [C16H13D3BrClN4O2 +H]+. Step-4: Synthesis of 1-bromo-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-2.1):
Figure imgf000098_0002
G-2.1 In a 1 L multi neck RBF, 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1, 15.00 g, 36.3 mmol.) and TFA (150 mL) was stirred for 3 h at 80 °C. After this time, the reaction mixture was cooled to room temperature and excess of TFA was distilled off to obtain crude viscous mass. The crude viscous mass was quenched with 10% NaOH solution and adjusted pH up to ~8. Solid was precipitated out, was filtered, and dried under vacuum, which was purified by column chromatography (silica gel, 5-10% MeOH/dichloromethane) to afford 1-bromo-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin- 8-amine (G-2.1, 7.00 g, yield: 73%) as an off white solid: ESI (m/z) 264 [C7H3D3BrClN4 +H]+. The compounds of formula G-2 (Table G) can be synthesized according to the procedures described for compound G-2.1: Table G: Compound G-2:
Figure imgf000099_0003
Scheme H:
Figure imgf000099_0001
H-1 H-2 Compounds of Formula H-2 where R5 = CF3, R3 = CH3, and Y1 = Br can be synthesized as described below for compound H-2.1: '
Figure imgf000099_0002
H-1.1 H-2.1 Synthesis of 1-bromo-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-8-amine (H-2.1):
Figure imgf000100_0001
H-2.1 To a stirred solution of 1-bromo-3-methylimidazo[1,5-a]pyrazin-8-amine (H-1.1, 5.00 g, 22 mmol) in acetonitrile (200 mL) were added Togni’s reagent (7.2 g, 22 mmol) followed by tris(trimethylsilyl)silane (6.2 g, 22 mmol) at room temperature and resulting reaction mixture was heated at 80 °C for 4 h. After this time, the reaction mixture was cooled to room temperature and excess of solvent was distilled off under reduced pressure to obtain crude material. The crude material was basified with aqueous ammonia solution, an aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was triturated with acetonitrile (20 mL) to obtain solid compound, was filtered and dried under vacuum to obtained 1-bromo-3- methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-8-amine (H-2.1, 3.20 g, yield: 50%) an off white solid; ESI (m/z) 295 [C8H6BrF3N4 +H]+. The compounds of formula H-2 (Table H) can be synthesized according to the procedures described for compound H-2.1: Table H: Compound H-2:
Figure imgf000100_0002
Scheme I: Synthesis of 1-bromo-8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-9):
Figure imgf000101_0001
Step-1: Synthesis of 2-aminomalonamide (I-2):
Figure imgf000101_0003
In a 450 mL autoclave, diethyl 2-aminomalonate hydrochloride (I-1, 36.00 g, 165.89 mmol) and ammonia solution (7 M in MeOH, 150 mL) was stirred for 20 h at room temperature. After this time, excess of MeOH was distilled off and dried under vacuum to afford 2-aminomalonamide (I-2, 19.00 g, yield: 95%) as a yellow solid (which was taken to next step without any purification): 1H NMR (400 MHz, DMSO- d6) G 7.51 (s, 2H), 7.24 (s, 1H), 3.71 (s, 1H), 2.30 (s, 2H); ESI (m/z) 118 [C3H7N3O2 +H]+. Step-2: Synthesis of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3):
Figure imgf000101_0002
To a stirred suspension of 2-aminomalonamide (I-2, 17.68 g, 151.16 mmol) and biacetyl (13 g, 151.16 mmol) in water (25 mL) was added aqueous NaOH (50% solution) (15 mL, 188.95 mmol) over a period of 20 min at 10 oC. After completion of addition, resulting reaction mixture was stirred for additional 2 h at the same temperature, pH of reaction mixture was adjusted to 6.0 (by acetic acid). The solid was precipitated out, was filtered and dried under vacuum to afford 5,6- dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3, 13.00 g, yield: 51%) as a light yellow solid: 1H NMR (400 MHz, DMSO- d6) G 13.22 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 2.38 (s, 3H), 2.32 (s, 3H); ESI (m/z) 168 [C7H9N3O2 +H]+. Step-3: Synthesis of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4):
Figure imgf000102_0001
To a stirred solution of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3, 12.00 g, 71.85 mmol) in chlorobenzene (60 mL) was added phosphoryl chloride (26.8 mL, 287.4 mmol) at room temperature. The resulting reaction mixture was heated to 60 oC and then added DIEA (37.57 mL, 215.55 mmol) dropwise over 30 min. Then the reaction mixture was stirred at 90 oC for another 3 h. After this time, the reaction mixture was cooled to room temperature, poured into mixture of sat. sodium bicarbonate solution (150 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 60% ethyl acetate/hexanes) to afford 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4, 8.31 g, yield: 69%) as a pale brown solid:
Figure imgf000102_0002
NMR (400 MHz, DMSO- d6) G 2.62 (s, 3H), 2.55 (s, 3H); ESI (m/z) 168 [C7H9N3O2 +H]+. Step-4: Synthesis of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5):
Figure imgf000102_0003
I-5 In 450 mL autoclave, to a stirred solution of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4, 8.00 g, 47.9 mmol) in acetic acid (150 mL) was added Raney Nickel (1.6 g) under inert atmosphere and resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (100 psi) at room temperature. After this time, the reaction mixture was passed through the celite bed and washed with acetic acid (2 × 20 mL). Excess of acetic acid was distilled off under reduced pressure, left behind viscous mass, poured into mixture of sat. sodium bicarbonate solution (150 mL) and ethyl acetate (200 mL).The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I- 5, 5.00 g, yield: 60%) as a green solid: 1H NMR (400 MHz, DMSO- d6) G 3.83 (s, 2H), 2.62 (s, 3H), 2.55 (s, 3H); ESI (m/z) 172 [C7H10ClN3 +H]+. Step-5: Synthesis of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl)acetamide (I-6):
Figure imgf000103_0001
To a stirred solution of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5, 5.00 g, 29.13 mmol) in dichloromethane (50 mL) was added DIEA (10.15 mL, 58.27 mmol) followed by acetic anhydride (5.5 mL, 58.27 mmol) at 0 °C. After, that reaction mixture was stirred for 2 h. After this time, the reaction mixture was diluted with dichloromethane (100 mL), washed with saturated NaCl solution (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexanes) to afford N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl) acetamide (I-6, 5.00 g, yield: 80%) as a yellow solid: 1H NMR (400 MHz, DMSO- d6) G 4.44 (d, J = 5.6 Hz, 2H), 3.40 (brs, 1H), 2.52 (s, 3H), 2.50 (s, 3H), 1.85 (s, 3H). Step-6: Synthesis of 8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-7):
Figure imgf000103_0002
To a stirred solution of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl) acetamide (I-6, 5.00 g, 29.94 mmol.) in acetonitrile (100 mL) were added dimethylformamide (0.50 mL) followed by phosphoryl chloride (8.3 mL, 153.3 mmol) at 0 °C. This reaction mixture was heated to 80 °C and stirred for 2 h. After this time, the reaction mixture was cooled to room temperature and poured into mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude materia! was purified by column chromatography (silica gel, 30% ethyl acetate/hexanes) to afford 8-chloro-3,5,6-trimethylimidazo[l,5-a]pyrazine (1-7, 3.50 g, yield: 77%) as a pale brown solid: 1H NMR (400 MHz, DMSO- d6) δ 7.67 (s, 1H), 2.90 (s, 3H), 2.70 (s, 3H), 2.30 (s, 3 H ) : ESI (m/z) 196 [C9H10ClN3 H ]+
Step-7: Synthesis of l-bromo-8-chIoro-3,5;6-trimethylimidazo[l,5-α]pyrazin e (I-8):
Figure imgf000104_0001
To a stirred solution of 8-chloro-3,5,6-trimethylimidazo[l,5-α]pyrazine (1-7, 5.00 g, 25.64 mmol) in dimethylformamide(50 mL) was added A-brornosuccinimide (4.56 g, 25.64 mmol) at 0 °C and stirred for 1 h. After this time, the reaction mixture rvas diluted with water (150 mL) and EtOAc (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 30% ethyl acetate/hexanes) to afford l-bromo-8-chloro-3,5,6-trimethylimidazo[l,5- ajpyrazine (1-8, 6.00 g, yield: 85%) as a pale yellow solid: 1H NMR (400 MHz, DMSO- de) d 2.90 (s, 3H), 2.70 (s, 3H) , 2.30 (s, 3H); ESI (m/z) 274 [C9H9B1-CIN3 H] .
Step-8: Synthesis of 1- bromo-8-chIoro-3,5,6-trimethyIimidazo[1,5-a]pyrazine (1-9):
Figure imgf000104_0002
In a 1 L autoclave, a mixture of l-bromo-8~chloro-3,5,6-trimethy!imidazo[l,5-α]pyrazine (I- 8, 6.00 g, 21.81 mmol) and ammonia (2M in isopropanol) (500 mL) was stirred for 12 h at 120 °C.
After this time, the reaction mixture was cooled to room temperature, excess of IP A was distilled off under reduced pressure to afford 1-bromo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (I-9, 4.50 g, yield: 81%) as a pale yellow solid: 1H NMR (400 MHz, DMSO- d6) G 6.33 (s, 2H), 2.81 (s, 3H), 2.60 (s, 3H), 2.12 (s, 3H); ESI (m/z) 255 [C9H11BrN4 +H]+. Scheme J: Synthesis of 3-(8-amino-1-bromo-6-methylimidazo[1,5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-2):
Figure imgf000105_0001
Step-1: Synthesis of (3-chloro-5-methylpyrazin-2-yl)methanamine (J-2): HCl
Figure imgf000105_0002
To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (J-1, 5.00 g, 3.26 mmol) in acetic acid (80.0 mL) was added Raney Nickel (1.55 g, 6.65 mmol.) under inert atmosphere. After completion of addition, resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (~30 psi) at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth, washed with EtOAc (2 × 100 mL). The organic layer was concentrated to obtain crude material, which was diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer was concentrated to obtain viscous mass was triturated with acetonitrile (5 mL) to afford (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 6.10 g, yield: 88%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+. Step-2: Synthesis of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3-oxocyclobutanecarboxamide (J-4):
Figure imgf000106_0001
To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 3.00 g, 26.3 mmol) in dichloromethane (80 mL) were added N,N-diisopropylethylamine (22.9 mL, 131.5 mmol), T3P (50% in EtOAc) (12 mL, 39.47 mmol) followed by 3-oxocyclobutanecarboxylic acid (J-3, 5.10 g, 26.31 mmol) at 0 oC and stirred for 1 h. After this time, the reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 × 50 mL) and brine (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was washed with hexanes to afford N-((3-chloro-5-methylpyrazin-2- yl) methyl)-3-oxo cyclobutanecarboxamide (J-4, 4.65 g, yield: 71%) as an off white solid; ESI (m/z) 254 [C11H12ClN3O2]+H]+. Step-3: Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-5):
Figure imgf000106_0002
To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3- oxocyclobutanecarboxamide (J-4, 4.70 g, 18.5 mmol) in EtOAc (80 mL) were added dimethylformamide (3 mL) followed by phosphoryl chloride (5.3 mL, 55.7 mmol) at 0 oC. This reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was cooled to room temperature and poured into mixture of sat. sodium carbonate solution (100 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was washed with hexanes to afford 3- (1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (J-5, 3.10 g, yield: 70%) as an off white solid; ESI (m/z) 236 [C11H10ClN3O+H ]+. Step-4: Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3-yl)cyclobutanone (J-6):
Figure imgf000107_0001
To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-5, 3.00 g, 12.7 mmol) in dimethylformamide (15 mL) was added N- Bromosuccinimide (2.21 g, 12.7 mmol.) at room temperature. This reaction mixture was stirred at room temperature for 40 min. After this time, ice cool water (50 ml) was added, solid was precipitated out, was filtered and dried to afford 3-(1-bromo-8-chloro-6-methylimidazo[1,5- a]pyrazin-3-yl)cyclobutanone (J-6, 3.30 g, yield: 82%) as an off white solid; ESI (m/z) 313 [C11H9BrClN3O+H ]+. Step-5: Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)-1- methylcyclobutanol (J-7):
Figure imgf000107_0002
To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3- yl)cyclobutanone (J-6, 3.30 g, 10.57 mmol) in anhydrous THF (35 mL) was charged methylmagnesium chloride (3M in THF) (7.1 mL, 21.15 mmol) dropwise at -78 °C over a period of 15 min under N2 and resulting mixture was stirred at -78 °C for an additional 2 h. After 2 h, then reaction mixture was warmed to –20 °C for 30 min. The mixture was cooled back to –78 °C, aqueous layer extracted with EtOAc (100 mL x 2), combined filtrate was washed with brine (50 mL). The combined organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 50% EtOAc in hexanes) to afford 3-(1-bromo-8-chloro-6-methylimidazo [1, 5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-7, 2.31 g, yield: 62%) as a white solid; ESI (m/z) 331 [C12H13BrClN3O+H ]+. Step-6: Synthesis of 3-(8-amino-1-bromo-6-methylimidazo[1,5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-8):
Figure imgf000108_0001
In a 450 mL autoclave, a mixture of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3- yl)-1-methylcyclobutanol (J-7, 1.50 g, 4.54 mmol) and ammonia (2M in isopropanol) (150 mL) was stirred for 18 h at 120 °C. After this time, the reaction mixture was cooled to room temperature, excess of solvent was distilled off to afford 3-(8-amino-1-bromo-6-methylimidazo [1, 5-a] pyrazin-3-yl)-1-methylcyclo butanol (J-8, 1.20 g, yield: 86%) as a pale brown solid; ESI (m/z) 312 [C12H15BrN4O+H ]+.
Figure imgf000108_0002
Compounds of Formula I can be synthesized according to the procedures for the synthesis of compound I.1 wherein R6 = methyl, R5 = H, R3 = methyl, Y1 = I, Ar2 = phenyl, R2 = 3-methyl, R3a = H, Ar1 = phenyl-R1 and R1 = 3-F:
Figure imgf000109_0001
Synthesis of N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide (I.1: Racemate, Example 3 and Example 4):
Figure imgf000109_0002
To a stirred solution of 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1, 0.120 g, 0.417 mmol) and 2-(3-fluorophenyl)-2-hydroxy-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetamide (D-1.1, 0.192 g, 0.5 mmol) in a mixture of N,N- dimethylformamide and H2O (8.0 mL, 8:2) was added potassium carbonate (0.115 g, 0.832 mmol) and degassed with argon for 5 min. >^^^ƍ-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.015 g, 0.020 mmol) was added and the reaction mixture was degassed with argon gas for 5 min. This reaction mixture was exposed to microwave irradiation (SEM Company) at 120 °C for 80 min. After this time, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2 x 5 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 1% methanol/methylene chloride) to afford N-(4-(8-amino-3,6-dimethylimidazo[1,5- a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide (I.1, 40 mg, yield: 22%) as a pale brown solid: ESI (m/z) 420 [C23H22FN5O2+H]+. The mixture of enantiomers was purified by chiral supercritical fluid chromatography (SFC) (Chiralcel® OX-H column, 30% methanol in CO2, 40 °C temperature) to afford: Isomer 1 (Example 3) as a pale brown solid: 1H NMR (400 MHz, DMSO-d6) G 10.05 (s, 1H), 7.69 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.42–7.34 (m, 3H), 7.18–7.11 (m, 2H), 6.63 (s, 2H), 6.35 (br s, 2H), 5.16 (s, 1H), 2.84 (s, 3H), 2.59 (s, 3H) 2.10 (s, 3H); ESI (m/z) 420 [C23H22FN5O2+H]+; HPLC (Method D) 99.0% (AUC), tR = 4.82 min; Chiral SFC (Chiralcel OJ-H, Method E) >99% (AUC), tR = 2.18 min. Isomer 2 (Example 4) as a pale brown solid: 1H NMR (400 MHz, DMSO-d6) G 10.05 (s, 1H), 7.69 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.42–7.34 (m, 3H), 7.18–7.11 (m, 2H), 6.63 (s, 2H), 6.35 (br s, 2H), 5.16 (s, 1H), 2.84 (s, 3H), 2.59 (s, 3H) 2.10 (s, 3H); ESI (m/z) 420 [C23H22FN5O2+H]+; HPLC (Method D) 97.9% (AUC), tR = 4.58 min; Chiral SFC (Chiralcel OJ-H, Method E) >99% (AUC), tR = 2.77 min. The compounds of formula I (Table 1) can be synthesized according to the procedures described in Scheme K: Table 1: Compounds of Formula I:
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
References Adrian L. Smith et al., Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), J. Med. Chem., 2015, 58 (3), pp 1426–1441 Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response Nat. Rev. Mol. Cell Biol. 2007, 8, 519– 529 Shore, G. C.; Papa, F. R.; Oakes, S. A. Signaling cell death from the endoplasmic reticulum stress response Curr. Opin. Cell Biol. 2011, 23, 143– 149 Carrara, M.; Prischi, F.; Ali, M. M. U. UPR signal activation by luminal sensor domains Int. J. Mol. Sci. 2013,14, 6454– 6466 Ma, Y.; Hendershot, L. M. The role of the unfolded protein response in tumor development: friend or foe? Nat. Rev. Cancer 2004, 4, 966– 977 Walter, P.; Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation Science2011, 334, 1081– 1086 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Janssens, S .; Heindryckx, F.; van Vlierberghe, H. The paradox of the unfolded protein response in cancer Anticancer Res.2013, 33, 4683– 4694 Gao, Y.; Sartori, D. J.; Li, C.; Yu, Q.-C.; Kushner, J. A.; Simon, M. C.; Diehl, J. A. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis Mol. Cell. Biol. 2012, 32, 5129–5139 Bi, M.; Naczki, C.; Koritzinsky, M.; Fels, D.; Blais, J.; Hu, N.; Harding, H.; Novoa, I.; Varia, M.; R aleigh, J.;Scheuner, D.; Kaufman, R. J.; Bell, J.; Ron, D.; Wouters, B. G.; Koumenis, C. ER stress- regulated translation increases tolerance to extreme hypoxia and promotes tumor growth EMBO J. 2005, 24, 3470–3481 Kim, I.; Xu, W.; Reed, J. C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities Nat. Rev. Drug Discovery 2008, 7, 1013– 1030 Fels, D. R.; Koumenis, C. 7KH^3(5.^H,)^Į^$7)^^PRGXOH^RI^WKH^835^LQ^K\SR[LD^UHVLVWDQFH^DQG^ tumor growth Cancer Biol. Ther. 2006, 5, 723– 728 Krähling, V.; Stein, D.A.; Spiegel, M.; Weber, F.; Mühlberger, E. Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity. J. Virol. 2009, 83, 2298–2309. Minakshi, R.; Padhan, K.; Rani, M.; Khan, N.; Ahmad, F.; Jameel, S. The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregulation of the Type 1 Interferon Receptor. PLoS ONE 2009, 4, e8342. Chan, C.-P.; Siu, K.-L.; Chin, K.-T.; Yuen, K.-Y.; Zheng, B.; Jin, D.-Y. Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. J. Virol. 2006, 80, 9279–9287. Siu, K.-L.; Chan, C.-P.; Kok, K.-H.; C-Y Woo, P.; Jin, D.-Y. Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus HKU1. Cell Biosci. 2014, 4, 1–9. WO2018/194885 U.S. Publication No. 2017/0165259 U.S. Patent No. 8,598,156

Claims

What is claimed is: 1. A method for treating a viral infection in a patient, comprising administering to said patient a therapeutically effective amount of a PERK inhibitor. 2. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of formula (I):
Figure imgf000169_0001
wherein: Ar1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R1 substituents; Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; Y is CR3aR3b, C(O), CF2, or CNOR3bb; R3a is H, alkyl, or cycloalkyl; R3b is H, alkyl, OR3c, or NR3dR3e; R3bb is H or alkyl; R4 is H, alkyl, or OH; X is CR7 or N; each R1 is independently H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, C0-6alkyl-O-C3-12cycloalkyl, or C0-6alkyl-O-C3-12heterocycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, CN, NO2, alkyl, C0-6alkylcycloalkyl, C0-6alkyl- O-C1-12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 or 2, wherein the PERK inhibitor is selected from a compound of formula (Ia):
Figure imgf000171_0001
wherein: Y is CR3aR3b; R3a is H or alkyl; R3b is OR3c or NR3dR3e; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkylcycloalkyl, C0-6alkyl-O-C1- 12alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents; X is CR7 or N; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1-3, wherein the PERK inhibitor is selected from a compound of formula (Ib):
Figure imgf000172_0001
wherein: X is CR7 or N; each R1 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, cycloalkyl, C0-6alkyl-O-C1-12alkyl, C0- 6alkyl-OH, or C0-6alkyl-O-C3-12cycloalkyl, optionally substituted by one or more independent G2 substituents; R3a is H or alkyl; R3b is OR3c or NR3dR3e; R3c, R3d and R3e are each independently H or alkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted by one or more independent H, deuterium or halo; ach G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0-12alkylC3- 12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1,
2,
3,
4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
5. The compound of method according to any one of claims 1-4, wherein the PERK inhibitor is selected from a compound of formula (Ic):
Figure imgf000174_0001
wherein: X is CR7; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G1 substituents; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent G2 substituents; R3b is OR3c; R3c is H or alkyl, optionally substituted by one or more independent G3 substituents; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G4 substituents; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, heteroaryl or alkyl, optionally substituted by one or more independent H, deuterium or halo; each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-12alkyl, C0- 12alkylC3-12cycloalkyl, C0-12alkylC3-12heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; R8, R9, or R10 are each independently selected from H, deuterium, halo, CN, NO2, alkyl, cycloalkyl and heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
6. The method according to any one of claims 1-5, wherein the PERK inhibitor is selected from a compound of formula (Id):
Figure imgf000175_0001
wherein: X is CR7; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, C1-6alkyl, halo, OH, or CN; R6 is H, alkyl, CD3, or CF3; R7 is H, deuterium, halo, alkyl, heteroaryl or CD3, wherein the alkyl may be optionally substituted by one or more halo substituents; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
7. The method according to any one of claims 1-6, wherein the PERK inhibitor is selected from a compound of formula (Ie):
Figure imgf000176_0001
wherein: X is CH; each R1 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium, or halo; each R2 is independently H, deuterium, halo, alkyl, C0-6alkyl-OH, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more independent H, deuterium or halo; R5 is H, deuterium, halo, methyl, ethyl, isopropyl, ,
Figure imgf000176_0002
optionally substituted by one or more independent H, deuterium, halo, OH, or CN; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
8. The method according to any one of claims 2-6, wherein R7 is H, chloro, methyl, ethyl, heteroaryl, trifluoromethyl, or CD3.
9. The method according to any one of claims 2-7, wherein each R1is independently H, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, fluoro, or chloro.
10. The method according to any of one of claims 2-7, wherein each R2 is independently H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, fluoro, chloro, CF3, or OCF3.
11. The method according to any one of claims 2-7, wherein R5 is H, chloro, methyl, CD3, ethyl, isopropyl,
Figure imgf000177_0001
.
12. The method according to any one of claims 2-6, wherein R6 is H, methyl, ethyl, propyl, isopropyl, CD3, or CF3.
13. The method according to any one of claims 2-5, wherein each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2.
14. The method according to any one of claims 2-5, wherein each G1, G2, G3, or G4 is independently H, deuterium, halo, CN, NO2, C1-3alkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2.
15. The method according to claim 2, wherein Ar1 is phenyl.
16. The method according to claim 2, wherein Ar2 is phenyl or pyridyl.
17. The method according to claim 1, wherein the PERK inhibitor is selected from a compound of the formula (If):
Figure imgf000178_0001
wherein: Ar2 is aryl or heteroaryl, optionally substituted by one or more independent R2 substituents; each R1 is independently halo or alkyl, optionally substituted by one or more halogen substituents; each R2 is independently halo, alkyl, or C0-6alkyl-O-C1-12alkyl, optionally substituted by one or more halogen substituents; R5 is alkyl or cycloalkyl, optionally substituted by one or more deuterium, hydroxyl or methyl substituents; R6 is H or alkyl; R7 is H, halo, or alkyl, optionally substituted by one or more halogen substituents; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.
18. The method according to claim 17, wherein p is 1.
19. The method according to claim 17 or 18, wherein each R1 is independently chloro, fluoro, methyl, or trifluoromethyl.
20. The method according to claim 17, wherein p is 2.
21. The method according to claim 17 or 20, wherein each R1is independently fluoro, methyl, or trifluoromethyl.
22. The method according to any one of claims 17-21, wherein Ar2 is phenyl.
23. The method according to any one of claims 17-21, wherein Ar2 is phenyl, optionally substituted by one substituent selected from R2.
24. The method according to claim 22, wherein each R2 is independently methyl, ethyl, fluoro, or trifluoromethoxy.
25. The method according to any one of claims 16-20, wherein Ar2 is phenyl, optionally substituted by two substituents each independently selected from R2.
26. The method according to claim 24, wherein each R2 is independently fluoro or methyl.
27. The method according to any one of claims 16-20, wherein Ar2 is pyridyl, optionally substituted by one substituent selected from R2.
28. The method according to claim 26, wherein R2 is methyl.
29. The method according to any one of claims 16-27, wherein R5 is methyl, CD3, or
Figure imgf000180_0001
.
30. The method according to any one of claims 16-28, wherein R6 is H or methyl.
31. The method according to any one of claims 16-29, wherein R7 is H, chloro, methyl, or trifluoromethyl.
32. The method according to claim 1, wherein the PERK inhibitor is a compound selected from the group consisting of: N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)- 2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5,6-trimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-(3-hydroxy-3-methylcyclobutyl)-6-methylimidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methyl-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl)-3- methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-5-chloro-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-methyl- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- methyl-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- methylphenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-5-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3-fluorophenyl)- 2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-ethylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(m- tolyl)acetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (m-tolyl)acetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (m-tolyl)acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-(m-tolyl)acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-(m-tolyl)acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-(m-tolyl)acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-phenyl]- 2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluorophenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2- fluorophenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2- fluorophenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro-phenyl]- 2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-(trifluoromethoxy)phenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3-chlorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-(3,5-difluorophenyl)-2-hydroxy-acetamide; N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3- difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-3-(trideuteriomethyl)-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl]- 2,3-difluoro-phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-5-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (R)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; (S)-N-[4-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-2,3-difluoro- phenyl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy-acetamide; N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3,5-dimethylimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-6-methyl-2- pyridyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide; N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-6-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (R)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; (S)-N-[5-[8-amino-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazin-1-yl]-4-methyl-2- pyridyl]-2-(3-fluorophenyl)-2-hydroxy-acetamide; or a pharmaceutically acceptable salt thereof.
33. The method according to any one of claims 1-32, wherein the compound or a pharmaceutically acceptable salt thereof is administered with one or more pharmaceutically acceptable carriers, diluents, or excipients.
34. The method according to any one of claims 1-33, wherein the viral infection is associated with a coronavirus.
35. The method according to claim 34, wherein the coronavirus is SARS-CoV, SARS-CoV-2 or MERS-CoV.
36. The method according to any one of claims 1-35, wherein the patient is a mammal.
37. The method according to any one of claims 1-36, wherein the patient is a human.
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